Tesis sobre el tema "Inhibiteurs CDK4"
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Richard, Mathilde. "Les vésicules extracellulaires plasmatiques, de potentiels biomarqueurs de suivi thérapeutique dans le cancer du sein métastatique". Electronic Thesis or Diss., Nantes Université, 2024. http://www.theses.fr/2024NANU1012.
Texto completoExtracellular vesicles (EVs), nanoparticle entities derived from cellular membranes, transport biological materials and circulate through body fluids. They are currently positioned as potential biomarkers for cancer progression and therapeutic response. Despite numerous innovative therapeutic strategies improving management and survival rates, breast cancer (BC) remains the leading cause of cancer-related death in women. Thus, the identification of specific biomarkers represents a significant hope for monitoring disease progression and predicting treatment efficacy. The primary objective of this research project was to characterize plasma EVs as potential biomarkers of response to CDK4/6 inhibitors treatment in metastatic breast cancer (MBC) patients with hormone receptor-positive (HR+) status. To facilitate translational research on the use of EVs as circulating biomarkers, we established a three-step procedure clinically applicable: 1- EVs were isolated from plasma using semi-automated size-exclusion chromatography (SEC); 2- plasma EV concentration (i.e., vesiclemia) was determined using the VideoDrop, a microscope utilizing interferometry; and 3- the sphingo-lipidic signature was analyzed by mass spectrometry. We initially measured vesiclemia in a healthy population to establish a reference value, accounting for sex and age. Subsequently, we monitored the physiological vesiclemia evolution over 24 months and compared it with that of MBC HR+ patients at different treatment stages. Our results reveal that an increase in vesiclemia two months after treatment initiation is significantly associated with early disease progression. Furthermore, we analyzed the lipid composition of EVs to reinforce their potential as biomarkers of disease progression. A specific signature of 16 EV-associated sphingolipids enabled us to establish a score identifying CDK4/6 inhibitor-resistant patients with82% accuracy. Finally, this characterization of plasma EVs as biomarkers led us to explore their potential in MBC patients with triple-negative and HER2+ status
Prevel, Camille. "Développement de biosenseurs fluorescents et d’inhibiteurs pour suivre et cibler CDK4/cycline D dans le mélanome". Thesis, Montpellier, 2015. http://www.theses.fr/2015MONT3505/document.
Texto completoCDK/cyclins play a central role in coordinating cell cycle progression, and in sustaining proliferation of cancer cells, thereby constituting established cancer biomarkers and attractive pharmacological targets. In particular, CDK4/cyclin D, which is responsible for coordinating cell cycle progression through G1 into S phase, is a relevant target in several cancers including melanoma, associated with mutation of CDK4, cyclin D, p16INK4a and pRb.As there are no sensitive and direct approaches to probe CDK4/cyclin D activity in physiological and pathological conditions, the first goal of my thesis has consisted in engineering a fluorescent biosensor to probe this kinase in vitro and in cellulo. Once characterized and validated in vitro, the biosensor was applied to detect CDK4/cyclin D alterations in biopsies from human skin and melanoma xenografts in fluorescence-based activity assays, and in living cancer cells by fluorescence microscopy and timelapse imaging.Moreover, only few inhibitors are currently available to target CDK4/cyclin D and most of them bind the ATP pocket. As such, the second major goal of my thesis project has consisted in identifying non-ATP competitive inhibitors, either through rational design of peptides or by screening small molecule libraries. To this aim, two fluorescent biosensors were engineered which discriminate compounds that target the interface between CDK4 and cyclin D, or that perturb the conformational dynamics of CDK4, respectively, from ATP-pocket binding compounds. Fluorescence-based screening assays performed with these biosensors lead to identification of hits, which were validated and characterized in vitro and in cell proliferation assays, and which constitute promising candidates for selective chemotherapy in melanoma
Delmas, Christelle. "Modes de régulation de l'inhibiteur de CDKs, p27kip1, par les MAPKsp42/p44". Toulouse 3, 2003. http://www.theses.fr/2003TOU30006.
Texto completoBacevic, Katarina. "Cdk2 as a model for studying evolutionary selection and therapeutic responses in proliferating cancer cells". Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT184.
Texto completoCyclin-dependent kinases (Cdk) are essential regulators of the cell cycle that support cell proliferation and are often deregulated in cancer. While Cdk1 is an essential regulator of the cell cycle, Cdk2 is not required for cell cycle progression but promotes tumorigenesis. Therefore, Cdk2 is a promising drug target. Many Cdk inhibitors have been developed and are currently undergoing clinical trials. Darwinian selection can be modelled mathematically, and such studies have shown that even marginal selective advantages can be of great importance in outcomes of cell-cell competition and cancer progression. We hypothesised that the non-essential role of Cdk2 for cell cycle progression may mean that it is a good target for cancer therapy as continual inhibition should be tolerated and should counteract deregulated cell proliferation in cancer. However, as with all chemotherapeutic agents, the development of clinical resistance is likely. We further hypothesized that applying a low-dose treatment with Cdk2 inhibitors should minimize chances of developing resistance, by maintaining competition between robustly proliferating cells that are sensitive to treatment, and resistant cells.The aim of the thesis was to investigate whether Cdk2 confers a proliferative advantage to cancer cells, whether cells can develop resistance to Cdk inhibitors, and if so, whether the mechanisms allowing resistance reduce cellular proliferative fitness.To answer these questions, we have created cell lines with varying degrees of resistance to a selective Cdk2 inhibitor (that at high doses, also inhibits Cdk1) and have characterised their proliferation capacity in comparison with parental cells and isogenic Cdk2 knockout cells. Although in these cells the Cdk2 gene is not mutated and the expression of Cdk2 protein remained unaltered, the kinase activity of Cdk2 is decreased. Similarly, Cdk2 gene knockout (Cdk2 KO) cells have reduced sensitivity to Cdk2 inhibition. Inhibitor-resistant cells proliferate efficiently but are outcompeted by parental, inhibitor-sensitive cells in competition experiments, confirming that inhibitor resistance entails a selective disadvantage. We found that the proliferation of both Cdk2 knockout and inhibitor-resistant (R50) cells is sensitive to nutrient and glucose depletion as well as hypoxia, despite a normal oxygen consumption rate, indicating increased aerobic glycolysis. R50 cells have highly upregulated Cdk6, which may contribute to resistance to Cdk2 inhibition. Moreover, they are sensitised to Cdk4/6 inhibition, which is currently authorised as a treatment for some classes of breast cancer. Finally, Cdk2 knockout cells have an impaired S-phase checkpoint. These results suggest that pharmacological inhibitors targeting Cdk2 might be synthetically lethal with other treatments, eg inhibition of DNA replication, of glycolysis, or of Cdk6. This might diminish cancer cell proliferation and prevent emergence of therapeutic resistance
Bettayeb, Karima. "Optimisation et caractérisation de nouveaux inhibiteurs pharmacologiques de kinases cycline-dépendantes (CDKs)". Rennes 1, 2008. http://www.theses.fr/2008REN1S025.
Texto completoCyclin-dependent kinases (CDKs) are key regulators of cell division cycle (CDK1, 2, 3, 4, 6, 7), apoptosis (CDK1, 5), and transcription (CDK7, 9). Pharmacological inhibitors of CDKs constitute a new family of potential antitumor agents: ten are under clinical trials, among which roscovitine, was discovered in our laboratory. My thesis is about identification, optimisation and characterization of biochemical and cellular effects of three new kinase inhibitory classes: 7-bromo-indirubins (7BIO), meriolin and new analogs of roscovitine (N&N1 and C&R8). 7BIO induces non-apoptotic cell death through an unknown mechanism (no release of cytochrome C, nor caspase activation). On the other hand, meriolins and second generation roscovitine analogs induce a classical apoptosis due to CDK9 inhibition, thus leading to disappearance of the cell survival factor, Mcl-1. These three classes of chemicals display promising anti-proliferative and antitumor properties
Bridoux, Lucie. "Effet de l’inhibiteur tissulaire des métalloprotéinases-1 (TIMP-1) dans les cellules érythroïdes normales et cancéreuses humaines. Caractérisation du récepteur". Reims, 2009. http://theses.univ-reims.fr/exl-doc/GED00001015.pdf.
Texto completoBesides its ability to inhibit MMP activity, TIMP-1 exhibits other biological functions such as mitogenic and anti-apoptotic effects on various cell lines. We showed that TIMP-1 induced UT-7 erythroid cell survival through activation of the JAK2/PI 3-kinase/Akt pathway. Recently, we showed that TIMP-1 specifically bound to pro-MMP-9 localized at the UT-7 plasmic membrane and that pro-MMP-9 membrane expression is crucial for TIMP-1 anti-apoptotic effect. In a first part, we showed that CD44 anchored pro-MMP-9 at the cell surface and that this protein played a crucial role in TIMP-1 anti-apoptotic effect since CD44 silencing abrogated pro-MMP-9 cell surface localisation and enabled TIMP-1-mediated cell survival. In TIMP-1 anti-apoptotic signalling pathway, JAK2 is the first tyrosin kinase phosphorylated following TIMP-1 stimulation. In a second part, we studied the interaction between CD44 and tyrosin kinase JAK2. We showed that CD44 is associated in a constitutive manner to JAK2 via the JAK2 FERM domain. Other kinases could be implicated in TIMP-1 anti-apoptotic pathway, among them the Src kinases. In a third part, we studied the implication of Lyn Src kinase in TIMP-1 effect. We showed that Lyn played a crucial role in TIMP-1 anti-apoptotic effect upstream the PI 3-kinase
Cot, Emilie. "Inhibition chimique des Cdk : mécanisme biochimiques et conséquences cellulaires". Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20054.
Texto completoCycline Dependant Kinases (Cdk) control cell cycle progression. The study of their roles is often difficult because of functional redundancy; when a given Cdk is absent, others may compensate. The main role of Cdk2 in the cell cycle is in the initiation of DNA replication, but absence of Cdk2 is compensated for by Cdk1. For example, mice with a genetic knockout of Cdk2 are viable. The chemical inhibition of Cdks may limit compensation by other Cdks. Therefore, to study Cdk2 roles, we have studied chemical inhibition by NU6102, which seems to be selective for Cdk2 in the Xenopus model. To verify the selectivity and study parameters that determine selectivity, we have designed and produced mutants of Cdk2 which are resistant to NU6102, allowing restoration of function in the presence of inhibitor. Moreover, we demonstrate in vitro that NU6102 is selective for Cdk2 compared to other human Cdks, and we describe phenotypes induced by NU6102 in cultured cells, which are interesting in the light of potential applications of NU6102 in cancer chemotherapy. Cdk activity is essential for initiation of DNA replication, but in metazoans no essential substrates are known. To identify potential Cdk substrates during DNA replication, we have performed a proteomics screen of the proteins loaded onto chromatin in the presence or absence of Cdk activity, in the Xenopus model. The results suggest that Cdk activity is not only required for assembling DNA replication complexes onto origins of replication, but may also be implicated in other cellular functions
Fourmentraux, Emmanuelle. "Modulation de l'activité lymphocytaire T CD4⁺ par le récepteur inhibiteur KIR2DL1". Paris 7, 2009. http://www.theses.fr/2009PA077022.
Texto completoThe functional activity of immune cells is controlled by a balance between activators and inhibitors signals. The Inhibitory killer Ig-like receptors (KIR) expressed on NK cells and memory effectors T-cell recognize the CMH-I molecules and inhibit cellular activation by SHP-1 recruitment. To better understand the fonction of KIR receptors on CD4⁺ T-cells, KIR2DL1 transfectants were obtained from human T-cell line and from primary CD4⁺ T-cells. Following TCR stimulation, IL-2 production is increased in CD4+ T cells transfected by KIR2DL1 independently of its engagement. When KIR2DL1 is engaged by its cognate ligand the TCR activation is inhibited. Co-stimulation of the TCR signaling by KIR2DL1 requires intact ITIM and their phosphorylation. It induces a subséquent SHP-2 recruitment and an increased of PKCθ and ERK phosphorylation. Synapses leading to activation are characterized by an increase in the recruitment of p-Tyr, SHP-2, and p-PKCθ. Interaction of KIR2DL1 with its ligand leads to a strong synaptic KIR2DL1 accumulation and SHP-1/SHP-2 recruitment resulting in the inhibition of TCR-induced IL-2 production. These data reveal that KIR2DL1 may induce two opposite signaling outputs in CD4⁺ T cells, depending on whether the KIR receptor is bound to its ligand. The unexpected results observed on the regulation of CD4⁺ T cells by KIR2DL1 receptors, through the functional duality of ITIM, is fundamental to determine the immune System capacity to develop an adapted answer, i. E. To maintain the balance between tolerance and immunity
Tikad, Abdellatif. "Développement de nouvelles pyrido[3,2-d]pyrimidines polyfonctionnalisées : application à la synthèse d’inhibiteurs de CDKs". Orléans, 2008. http://www.theses.fr/2008ORLE2079.
Texto completoPouche, Lucie. "Variabilité d'origine génétique et épigénétique de la pharmacodynamie des inhibiteurs de la calcineurine en transplantation rénale". Thesis, Limoges, 2016. http://www.theses.fr/2016LIMO0017/document.
Texto completoInter-individual genetic variation might account for diverse efficacy and toxicity of calcineurin inhibitors (cyclosporin and tacrolimus). In particular, some variants located within genes coding for proteins of the calcineurin pathway can explain part of this variability. In this manuscript, a panel of candidate genes was selected based on bibliographic review and tested in a pharmacogenetics study encompassing 381 renal transplants followed for one year after surgery. None of these candidates was associated with the acute rejection or serious infection risks. Furthermore, the pharmacodynamic variability of these drugs was also investigated, exploring the use of epigenomics profiling as proximal readout of the calcineurin inhibition treatment. In particular, we investigated the impact of drug exposure on DNA methylation in two experimental models. Methylated DNA immunoprecipitation followed by high-throughput sequencing (MeDIP-seq, Ion Proton technology) was deployed in JURKAT cell line, used as in vitro model, and in CD4 T lymphocytes isolated from mice treated with either cyclosporin or tacrolimus for three months. After sequencing, the differentiated methylated regions caused by drug exposure were analyzed. Bioinformatics analyses were performed using SAMtools (Li et al., 2009), BEDtools (Quinlan and Hall, 2010), MACS2 (Zhang et al., 2008) and Diffbind (Stark and Brown, 2011 - Bioconductor). Overall, the genome-wide analysis revealed only 24 regions with a differentiated enrichment in DNA methylation after three month-tacrolimus treatment, indicating a targeted effect of these treatments on a subset of key genes. Of note, CALM2 promoter, coding for the calmodulin isoform 2 protein, showed significant hypermethylation in tacrolimus-treated mice. These preliminary results corroborate the interest in using DNA methylation as promising approach to identify candidate biomarkers for therapeutic drug monitoring in calcineurin inhibitor treatments
Sarkis, Manal. "Les phosphates CDC25 constituent-elles des cibles importantes en cancérologie : Des inhibiteurs de l'activité enzymatique vers les inhibiteurs de l'interaction entre CDC25 et leurs substrats CDK-Cycline". Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05P635.
Texto completoCDC25 phosphatases are key regulators of the cell cycle and its checkpoints. Hence, they are required to dephosphorylate and thus activate the Cdk/Cyclin complexes triggering progression through the different phases. Over-expression of CDC25 has been demonstrated in a large number of human tumors and is often associated with aggressiveness and poor clinical prognosis. CDC25 phosphatases may therefore represent attractive targets for anti-cancer therapy. Starting from a thiazolopyrimidinone (TZP) structure, previously reported as CDC25 inhibitor in our laboratory, two series of new compounds have been developed. Dimerisation of the thiazolone scaffold led to bis-thiazolone derivatives with inhibitory activities in the micromolar range greater than that observed for the mono-thiazolones. Moreover, most of these compounds were selective CDC25 inhibitors. A second scaffold was designed by opening of the pyrimidine ring of the TZP, leading to thiazolidine-4-one derivatives that inhibit CDC25B activities with values of IC50 in the micromolar range. A four-component reaction, using micro-wave irradiation, was developed to rapidly prepare these compounds. Finally, an approach aiming at inhibiting the interactions between phosphatase CDC25 and its substrate CDK2 was engaged. Several virtual chemical libraries will be screened in silico, and the small molecules candidates selected will be assessed for their binding affinity using an in vitro assay, that we sought to develop
Nafati, Mehdi. "Caractérisation fonctionnelle des inhibiteurs de Cyclin-Dependent Kinase (CDK) dans le fruit de tomate (Solanum lycopersicum)". Thesis, Bordeaux 2, 2010. http://www.theses.fr/2010BOR21712/document.
Texto completoWithin the Joint Research Unit 619 of the National Institute of Agronomic Research (INRA), the group "Organogenesis of the Fruit and endoreduplication" examines the molecular players involved in cell cycle control in tomato fruit. The purpose of this thesis is the study of the cell cycle inhibitor Kip-Related Protein and its role during fruit development. Identification of protein motifs in the functional inhibitor of Cyclin-Dependent Kinase in Solanum lycopersicum SlKRP1: Their role in interactions with partners in the cell cycle The Kip-related proteins (KRPs) play a major role in the regulation of cell cycle. It has been shown to inhibit the CDK / Cyclin and thus block cell cycle progression. Despite their lack of homology with their counterparts in animals beyond their binding motif CDK / Cyclin, located at the C-terminal protein sequences in the plant, previous studies have shown the presence of conserved motifs plant specific in some KRPs, but there is little information about their function. We show here that the KRPs are distributed into two phylogenetic groups, and that each subgroup has specific short conserved motifs. The KRPs from subgroup 1 have six conserved motifs. Using SlKRP1, which belongs to subgroup 1, we have identified the motifs responsible for the localization of the protein and protein-protein interactions. We demonstrate that the pattern 2 is responsible for the interaction with CSN5, a subunit of the signalosome complex, and that the motif 5 is redundant with motif 3 with respect to the sub-cellular localization of the protein. We also show that SlKRP1 is capable of guiding SlCDKA1 and SlCycD3; 1 to the nucleus, even in the absence of CDK / cyclin binding motif previously referenced. This new site of interaction is probably located in the central part of the sequence of SlKRP1. These results provide new clues about the role of the little-known part of this protein. Overexpression of SlKRP1 in tomato mesocarp disrupts the proportionality between endoreduplication and cell size The fruit is a specialized organ which results from the ovary after pollination and fertilization, and provides a suitable environment for seed maturation and dispersal. Because of their importance in human nutrition and economic importance, fleshy fruit species have been the subject of study mainly focused on the developmental formation of the ovary, fruit set and fruit ripening. The stage of fruit growth has been much less studied, although cell division and cell growth taking place during this period are crucial to determining the final size of the fruit, as well as its mass and shape. The development of tomato fruit mesocarp occurs by the estate of a phase of cell division followed by a phase of cell expansion associated with endoreduplication, leading to the formation of giant cells (up to 0.5 mm) with ploidy levels of up to 256C. Although a clear relationship between endoreduplication and cell growth has been shown by many examples in plants, the exact role of endoreduplication has still not been elucidated, since most of the experiments leading to a change in the level of endoreduplication in plants also affected cell division. We studied the kinetics of the development of tomato mesocarp morphologically and cytologically and studied the effect of the reduced level of endoreduplication in the development of the fruit over-expressing the cell cycle inhibitor Kip-Related Protein 1 (SlKRP1) specifically in the growing cells of the tomato mesocarp. We show a direct proportionality between endoreduplication and cell size during normal development of the fruit, which allowed us to build a model for development of mesocarp defining the thickness of the pericarp by taking into account the number of cell divisions and the number of rounds of endoreduplication. Surprisingly, the tomato mesocarps affected in their level of endoreduplication by over-expression of SlKRP1 are not affected in terms of cell size and fruit, or on their metabolic content. Our results demonstrate for the first time that while the level of ploidy is closely linked with cell size and fruit, endoreduplication is not responsible for the cell growth of tomato mesocarp
Jasinski-Grondard, Sophie. "Caractérisation d'un inhibiteur de kinases cycline-dépendantes de N. Tomentosiformis : analyse de son rôle au cours du développement de la plante". Paris 11, 2002. http://www.theses.fr/2002PA112272.
Texto completoPlant development requires stringent controls between cell proliferation and cell differentiation. Proliferation is positively regulated by cyclin dependent kinases (CDKs), whose activity is regulated at several levels including inhibition by CDK inhibitors (CKIs). The screen of a two-hybrid BY-2 cell suspension library with a CDKA as a bait, allows the isolation of two cDNA, named NtKIS1a and NtKIS1b. NtKIS1a and NtKIS1b mRNAs arise from the same N. Tomentosiformis gene by alternative splicing. The deduced polypeptide from NtKIS1a shares strong sequence similarity with mammalian CIP/KIP inhibitors, which is not the case for NtKIS1b. Consistent with this, NtKIS1a but not NtKIS1b inhibits in vitro the kinase activity of CDK/cyclin complexes. To gain insight into the role of NtKIS1a and NtKIS1b during plant development, their overexpression in different species was achieved. Arabidopsis thaliana plants overexpressing NtKIS1b display a wild type phenotype, whereas plants overexpressing NtKIS1a display strong morphological modifications. Our results suggest that the inhibition of cell division is responsible for the phenotypic modifications and thus that NtKIS1a is a cell division inhibitor in planta. Plants overexpressing simultaneously NtKIS1a and AtCycD3;1 were achieved. Their analyze demonstrates that overexpression of the CKI NtKIS1a restores essentially normal development in AtCycD3;1 overexpressing plants, providing for the first time, evidence of Cyclin D-CKI co-operation within the context of a living plant. At the aim of highlighting the links between cell cycle and development, the expression of two genes was modify simultaneously in planta: KNAT1 (knotted1-like from Arabidopsis thaliana) involved in shoot apical meristem development and function, and NtKIS1a involved in cell cycle regulation. The analysis of the F1 plants shows that co-expression of NtKIS1a and KNAT1 enhance the KNAT1 phenotype, suggesting that the two gene products co-operate with each other during plant development
Vandromme, Lucie. "Synthèse de purines trisubstituées en tant qu'inhibiteurs potentiels d'enzymes : application à l'inhibition des protéines kinases dépendantes des cyclines (CDK)". Paris 11, 2005. http://www.theses.fr/2005PA112160.
Texto completoCDK are key regulatory of cell cycle enzymes and their deregulation is involved in cancer. Therefore, they are targets of choice for cancer therapy. In the laboratory, researches are focused on the synthesis of powerful and specific CDK inhibitors. Effective synthetic inhibitors have been discovered despite the great structural similarity between each CDK, and purines are one of several families which include the most specific inhibitors. The synthesis of 2,6,9-trisubstituted purines as potential CDK inhibitors is carried out by parallel synthesis. This strategy was applied in solution at first, and should be optimized on resin to lead then to supported syntheses of libraries. This thesis deals with synthesis of new original purine libraries obtained by palladium coupling reactions, and their biological evaluation. Thus, after rection conditions optimization, new purines have been obtained using Suzuki, Sonogashira, amidation or carbonylation reactions. Then their CDK inhibitory activity has been tested. As a first approach on solid support, the influence of the spacer arm length in some palladium coupling reactions has been studied
Esvan, Yannick. "Conception et synthèse de nouveaux composés hétéroaromatiques inhibiteurs potentiels de kinases". Thesis, Clermont-Ferrand 2, 2016. http://www.theses.fr/2016CLF22743.
Texto completoIn 1950’s protein kinases were found to play a critical role in cell signaling, rising strong research potential for this enzyme family. Initially investigated for their implications in cancerogenesis they were more recently found to be involved in a wide variety of diseases including neurodegenerative pathologies. Herein will be presented two research projects that offer bright new perspectives for the inhibition of kinases involved whether in neurodegenerative diseases or cancers.First, the design and synthesis of new pyrido[3,4-g]quinazoline derivatives will be described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A) that are known to play a potential role in Alzheimer’s disease. The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/ DYRK1A activity was validated by nanomolar potencies. CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket and led to the synthesis of new diversely substituted pyrido[3,4-g]quinazolines.Then the synthesis of a new derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, will be depicted. The resulting indolopyrazolocarbazole inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ . The lead compound exhibited same cytotoxic activity as K252c toward both human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with kinases activities
Peyressatre, Marion. "Développement de biosenseurs fluorescents et d’inhibiteurs pour suivre et cibler CDK5/p25 dans le glioblastome". Thesis, Montpellier, 2016. http://www.theses.fr/2016MONT3513/document.
Texto completoCDK5 is a protein kinase ubiquitously expressed but mainly activated in the central nervous system, where it plays an important role in neuronal functions such as synaptic transmission, axonal guidance and migration, synaptic plasticity and neuronal development. CDK5 is associated with p35 protein at the cell membrane, then activated by calpain-mediated cleavage of p35 into p25, which promotes relocalization of CDK5/p25 into the cytoplasm. CDK5/p25 phosphorylates a wide variety of substrates including Tau, thereby contributing to appearance of neurofibrillary plaques responsable for neurodegenerative pathologies such as comme Alzheimer’s et Parkinson’s, when hyperactivated. More recent studies suggest that CDK5 expression and hyperactivation are involved in glioblastoma during cell invasion and CDK5 expression has been reported to be correlated with the pathological grade of gliomas. However there are currently no tools available to monitor CDK5/p25 activity in its native cellular environment, in tissues or in tumours, due to an overall lack of reliable tools to quantify dynamic changes in its kinase activity in a sensitive and continuous fashion. Furthermore, few inhibitors are currently available to target CDK5/p25 in a specific fashion and most of them are ATP competitive inhibitors.The first goal of my thesis was to develop a fluorescent peptide biosensor named CDKACT5, that specifically reports on recombinant CDK5/p25 and on endogenous CDK5 activity in cell extracts in a dynamic and reversible fashion following stimulation or inhibition of this kinase. Once validated in vitro, this biosensor was applied to detect alterations in CDK5/p25 activity in different glioblastoma cell lines in fluorescent kinase activity assays. Finally CDKACT5 was introduced into cultured neuronal cells to monitor dynamic changes in CDK5/p25 activity by fluorescence imaging and time-lapse microscopy.The second goal of my thesis project consisted in developing a conformational fluorescent biosensor to identify non-ATP competitive inhibitors targeting the activation loop of CDK5. CDKCONF5 was implemented to perform a high throughput screen of three small molecule libraries. The hits identified were validated and characterized to determine their inhibitory potential in kinase activity and proliferation assays, as well as their mechanism of action. These compounds constitute promising for selective chemotherapy in glioblastoma
Millan, Laurine. "Caractérisation d’inhibiteurs de complexes CDK‐cycline chez Arabidopsis thaliana". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112149.
Texto completoAs in all multicellular organisms, growth and development in plants require the coordination of cell production by division and cell differentiation. Progression through cell cycle is controlled by the kinase activity of CDK/cyclin complexes. Inhibitors of these complexes, CKIs, represent excellent candidates to regulate the balance between proliferation and differentiation processes during development. To get insight in the potential integrator role of CKIs, floral development was chosen as a developmental model. Using a real time quantitative PCR approach, we bring to light that during floral development of Arabidopsis thaliana, a restricted subset of CKIs was preferentially expressed. It was decided to focus our work on the two major expressed CKIs, KRP6 and KRP7. A better characterization of their expression patterns of during development was undertaken using complementary approaches such as promoter activity analysis, mRNA dynamics, protein expression and post-translational regulation analysis. Because until now ‘gain of function’ approaches have been largely applied to unravel the role of plant CKIs, our challenge was to detect a floral phenotype for KRP6 and KRP7 loss of function mutants, either using knock-out mutants or RNAi lines. We generated krp6-krp7, krp3-krp6, krp3-krp7 double mutants and krp3-krp6-krp7 triple mutant and also several RNAi lines with specifics promoters. Despite the study of these numerous lines, we were not able to highlight phenotypic effects associated with the absence of CKI function during floral development. All these results emphasis functional redundancy which appears to exist between all KRPs, thus quadruple mutant might be needed to provoke some developmental modification.In order to better understand the integrative function of KRPs during floral development, partners of KRP6 and KRP7 were assessed. Two-hybrid screens were performed to identify cDNAs from a “floral-buds-development” library encoding proteins that are able to interact with KRP6 and KRP7. Interestingly, apart from D-type cyclins, we brought to light a new type of interaction. Indeed, a sub-class of the remorin protein family was able to interact with KRP6 or KRP7 in yeast two-hybrid. Remorins are plant specific plasma membrane associated proteins with unknown function. A BiFC approach in BY-2 protoplasts allowed us to confirm remorins/KRP6-7 interactions. Furthermore, the influence of the presence of remorin proteins on KRP6/7 localisation was assessed. KRP7 is able to adopt a nucleo-cytoplasmic localisation in presence of its new partners.Finally, recent results have shown that AMPK is phosphorylating p27KIP1, KRPs functional counterpart in mammals. These phosphorylation events lead to changes in its cellular localisation and its inhibitory activity toward CDK-cyclin complexes. After in silico analysis aiming to predict potential AMPK Arabidopsis homologue SnRK1 phosphorylation sites within some KRPs protein sequences, recombinant KRP6 was used in order to perform in vitro kinase assays. Phosphorylation occurs efficiently on KRP6 when activated SnRK1 catalytic subunit is present. Furthermore, unlike in mammals, this phosphorylation event leads to an alteration of KRP6 inhibitory activity without modification of its cellular localisation. This abolition of KRP6 activity was confirmed by in planta analysis. Indeed, KRP6 overexpression phenotype can be attenuated by simultaneous SnRK1 catalytic subunit overexpression. The existence of this link between KRP6 and SnRK1 underscores a direct relationship between energy homeostasis and cell proliferation
Vigneron, Céline. "Rôle des inhibiteurs de CDK dans la différenciation conjointe de l'ovocyte et des cellules du cumulus chez le bovin". Tours, 2003. http://www.theses.fr/2003TOUR4021.
Texto completoIn bovine, oocytes which are blocked in meiotic prophase acquire sequentially their competence to resume and complete meiosis and the potential for development. This period of oocyte terminal differentiation allows the storage of maternal RNA and proteins necessary for embryos development. In vitro, as son as extracted from their follicular environment, oocytes spontaneously resume meiosis. A preliminary culture allowing the maintenance of oocytes at meiotic prophase might allow them to complete this differentiation step in vitro. We showed that the use of roscovitine allowed maintaining oocytes in meiotic block without loss of developmental potential, nor cumulus cells functionalities. This work will allow improving the culture conditions of bovine oocytes in order to increase their final developmental competence and will allow a better understanding the mechanisms of meiosis resumption control in oocytes and to distinguish between the events that are related to MPF activation or not in this complex process
Hamdi, Amel. "Découverte de petites molécules inhibitrices d’interactions protéiques : développements méthodologiques et application à l’interaction CDK2/CKS1". Rennes 1, 2012. http://www.theses.fr/2012REN1S128.
Texto completoSmall molecule inhibitors of protein interactions are invaluable research tools, enabling a better understanding of regulatory mechanisms. In addition, protein interaction networks represent a relatively untapped, rich source of potential therapeutic targets. Therefore, it is likely that many inhibitors of protein interactions may also represent therapeutic candidates of interest. The discovery of small-molecule inhibitors of protein interactions has been generally considered as an arduous if not impossible task in the past century. However, in the past decade, it has become increasingly popular, partly thanks to the availability of a large arsenal of valuable screening methods. One of the objectives of the PhD work was to optimize a yeast BRET assay (Bioluminescence Resonance Energy Transfer) previously developed in our lab. Although this work has not brought the expected optimization, it has provided a better understanding of the assay in yeast and it has suggested new avenues of optimization. The other objective was to discover small-molecule inhibitors of the interaction between CDK2, a protein kinase that plays a key role in cell division, and the CKS1 regulatory protein. CKS proteins interact with CDK1/2-Cyclin complexes and play multiple roles in regulating the cell cycle and in maintaining mitochondrial genome integrity. Two small-molecule inhibitors of the interaction CDK2/CKS1 were identified by screening a chemical library, using a yeast two-hybrid assay. They have been confirmed by in vitro interaction assays and more active analogues have been identified
Bendjeddou, Lyamin. "Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P615.
Texto completoPhosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo
Trouvilliez, Sarah. "Caractérisation des interactions entre TrkA, CD44 et les molécules de leur signalisation dans les cancers du sein triple négatifs". Electronic Thesis or Diss., Université de Lille (2022-....), 2022. http://www.theses.fr/2022ULILS104.
Texto completoBreast cancer is the most common malignancy in women worldwide (WHO). Breast cancer is a heterogeneous disease and prognosis varies according to molecular characteristics. In particular, the management of triple-negative breast cancer (TNBC) remains a clinical challenge due to the lack of specific and effective therapy. In this context, our team has highlighted the role of TrkA in TNBC. More precisely, the work of Prof. Toillon shows that TrkA acts not only via its phosphorylation but also via the membrane receptor platform. In particular, NGF induces an interaction of TrkA with the glycoprotein CD44. The TrkA/CD44 complex activates a TrkA phospho-ndependent signaling involved in the resistance of TrkA inhibitors. To target this resistance mechanism, the interactions between TrkA, CD44 and their signaling partners were investigated. First, I determined that the TrkA/CD44 complex involves only CD44 variant 3. By determining the molecular motifs involved, a peptide blocking the TrkA/CD44v3 association was synthesized and an H112A mutant of TrkA. I thus confirmed the importance of the amino acids of CD44v3 (IDDDEDFISST) and of the amino acid H112 on TrkA in this interaction. Interestingly, this blocking peptide reduces tumor growth and metastasis. Furthermore, we showed that CD44 inhibition does not affect the binding of one of TrkA/CD44 signaling partners. We then deciphered the TrkA/signaling molecule interaction and showed that an inhibitor of this interaction blocks the migration of triple negative cancer cells. In conclusion, our studies revealed the role of TrkA/CD44/signaling molecule interactions in breast cancer aggressiveness and resistance to TrkA inhibitors. It suggests that if current TrkA inhibitors are not effective in TNBC, novel inhibitors disrupting TrkA/CD44 signaling could be a new therapeutic option
Beziaud, Laurent. "Impact des inhibiteurs de la voie mTOR sur la réponse immunitaire T anti-tumorale". Thesis, Besançon, 2015. http://www.theses.fr/2015BESA3002.
Texto completoThe mammalian Target of Rapamycin (mTOR) pathway plays a central role in the regulation of cell growth andmetabolism, and is involved in oncogenesis. Everolimus and temsirolimus are two mTOR inhibitors (mTORi) approvedfor renal and breast carcinoma treatments. However, accumulating evidence highlights a central role for mTOR pathwayin T cell immunity. We showed that 21 out of 23 metastatic renal cell carcinoma patients under everolimus treatmenthad an increase of Tregs atter everolimus treatment. Paradoxically, strong antitumor Th 1 responses were detected andthen greatly decreased at the time of disease progression when high expansion of Tregs occurred. Furthermore, weidentified three immune groups based on the early modulation of both Treg and anti-tumor Thl cells and found thatpatients with {low Tregs plus high anti-tumor Thl cells} showed the best survival. In vitro, mTORi-exposed Tregs highlysuppressed T cell proliferation and Thl-associated cytokines production. We showed in vivo that T cells depletiondifferentially modulated the antitumor efficacy of mTORi. Although anti-mTOR effect was loss in B16-OVA-bearingmice lacking CD8 T cells, CD4 T depletion increased mTORi efficacy. The studies conducted in mice demonstratedthat the presence of Tregs in vivo altered the responses to mTORi via a mechanism involving the inhibition of antitumorCD8 T cell responses. Finally the efficacy of mTORi was improved by combination with Tregs depleting agents andvaccines. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T cell immunity onthe clinical effectiveness of mTQRi and prompt their association with immunotherapies
Bourderioux, Aurélie. "Synthèse d'hybrides d'indolocarbazoles et de la caulersine, composés à visée antitumorale". Phd thesis, Université d'Orléans, 2007. http://tel.archives-ouvertes.fr/tel-00147916.
Texto completoDans le cadre de la recherche de nouveaux agents cytotoxiques et d'inhibiteurs de kinases toujours plus sélectifs, la structure principale des phénylcarbazoles, appartenant à la famille des indolocarbazoles, a été modifiée par introduction d'une tropone centrale, cycle à 7 chaînons porteur d'une fonction carbonyle. Les différentes voies de synthèse permettant d'accéder à cette nouvelle famille de composés appelés oxophénylarcyriaflavines ont été étudiées. La méthode de choix retenue pour l'étape finale de la synthèse est la cyclisation électrophile en position 2 de l'indole. Cette synthèse a ensuite été généralisée aux composés substitués par des groupements hydroxyles en position 5 de l'indole d'une part et en position 4' et 5' du noyau phényle d'autre part. Les 17 molécules finales ainsi synthétisées ont subi divers tests biologiques permettant d'établir les RSA de cette nouvelle famille de composés. Finalement, la méthodologie mise au point pour les oxophénylarcyriaflavines a été étendue à la synthèse de la toute première famille de composés bisindoliques possédant également une tropone centrale.
Pellegatti, Laurent. "Méthodologie en chimie hétérocyclique et application à la synthèse d'inhibiteurs de kinases". Thesis, Orléans, 2010. http://www.theses.fr/2010ORLE2046.
Texto completoCancer, one of the leading causes of death, represents today a major public health problem. Over the last few years, marine alkaloids represent a source of inspiration for chemists in order to obtain new anticancer drugs. For this purpose, as a part of our laboratory researches, analogues of marine alkaloids were synthesized possessing a tris-aromatic structure. We developed originals analogs of these alacaloïds formed by a central heterocycle core (1,2,4-triazine et imidazo[1,2-b][1,2,4,5]tetrazine) on wich is graft two arylic moiety variously substituted. Obtaining these compounds was also an opportunity to develop news synthetic methodologies. So a new Buchwald-Hartwig reaction type based on methylsulfanyl-1,2,4-triazines has been perfect, as palladocatalyzed CH arylation pathway on imidazo[1,2-b][1,2,4,5]tetrazine. A part is devoted to Groebke-Blackburn multicomponant reaction. Various pharmacological analyses were carried out in particular with inhibition of various kinases and cytotoxicity evaluation on various human cancer cell lines
Colin, Philippe. "Etude de la diversité des interactions des souches R5 du VIH-1 à CD4 et CCR5 : Conséquences sur l'infectivité des virus et leur susceptibilité aux inhibiteurs de l'entrée". Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC169.
Texto completoCCR5 is a seven-transmembrane domain G-protein coupled receptor, which binds the chemokines CCL3, CCL4 and CCL5 (R5-CHKs), regulates migration and activation of leukocytes and contributes to the innate immunity and the initiation of adaptative immune responses. The receptor is also a CD4-associated coreceptor required for human immunodeficiency virus type 1 (HIV-1) entry into CD4 T-lymphocytes and macrophages. R5-CHKs have anti-HIV activity in vitro, both by competing with the viral envelope glycoprotein gp120 for binding to CCR5 and by promoting CCR5 downregulation, suggesting that they act as a natural barrier against HIV in vivo. We provide insights into how the multiplicity of CCR5 forms influences the anti-HIV-1 activity of R5-CHKs as well as the ability of HIV-1 variants to infect target cells. We showed that R5-CHKs exert poor antiviral activities, while they have higher affinities for CCR5 than R5 gp120, suggesting a viral escape from inhibition. We explained this in terms of CCR5 adopting a G-protein uncoupled, low-chemokine affinity conformation at the cell surface, which is utilized by R5¬HIV-1 to enter into cells and engaged by R5-chemokines for CCR5 downregulation. We showed that multiple CCR5 populations were differentially recognized by different gp120, which may impact HIV entry. Our results shed light to mechanisms regulating the phenotypic properties of R5 viruses' evolution during HIV infection. In particular, they demonstrated how the viruses exploit the heterogeneity of CCR5 conformations to infect their target cells and escape to viral entry inhibitors
Lossaint, Gérald. "Mécanismes orchestrant la sortie du cycle cellulaire opérant en G2". Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20040/document.
Texto completoCancer is a multi-step process resulting from abrogation of several barriers to uncontrolled proliferation. They include inhibitory pathways with appropriate checkpoints that lead to reversible (quiescence) or irreversible (senescence, apoptosis) block of cell proliferation. We are especially interested in pathways orchestrating cell cycle exit that operate in the G2 phase. The first objective of this thesis was to decipher mechanisms that prevent mitosis in response to DNA damage. We found that Cdk inhibitor p21Waf1 plays a crucial role in blocking mitotic onset in normal cells; acting in tandem with checkpoint kinase Chk1, p21 inactivates mitotic Cdks and inhibits pRb phosphorylation, thereby irreversibly blocking mitotic entry. In contrast, in p53-proficient transformed cells, the induction of p21 in G2 is impaired, most likely because of deficient ATM activation. While, in some cases, Chk1 hyper-activation prevents mitosis, the absence of p21 compromises the senescence program from G2. Finally, we showed that Chk2 is dispensable for G2 arrest in both non-transformed and transformed cells (Lossaint et al., submitted). Our second objective was to elucidate the pathways that induce quiescence (G0). This reversible cell cycle exit occurs in G1, requires pRb family members and p27Kip1-dependent Cdk inactivation. Based on observations obtained in our team and the data in the literature, we hypothesized that reversible cell cycle exit program might be launched before mitosis. By using an in vitro wounding model, we showed that confluence-driven quiescence is preceded by pre-mitotic CDK inhibition by p27, cyclin D1 downregulation and reduced pre-mitotic pRb phosphorylation (Chassot et al., 2008). Moreover, our results obtained in synchronized fibroblasts that were serum-starved after release from G1/S block suggest that cyclin D1 might stimulate proliferation by keeping pocket proteins phosphorylated during G2/M progression (Lossaint et al., in preparation)
Borgne, Annie. "Etude de la regulation de cdc2/cycline b a la transition prophase/metaphase de l'ovocyte d'etoile de mer. Caracterisation des effets de la roscovitine, un nouvel inhibiteur chimique de cdk". Paris 6, 1998. http://www.theses.fr/1998PA066422.
Texto completoLévêque, Romain. "Plasticité des réseaux de récepteurs membranaires dans la signalisation du NGF et de son précurseur dans les cancers du sein". Thesis, Lille, 2019. http://www.theses.fr/2019LIL1S102.
Texto completoINSERM U908 lab highlighted the role of NGF in breast cancer aggressiveness through the activation of its receptor TrkA. Previous works demonstrated that inhibition of TrkA activity contributes to a significant decrease of the tumors size in vitro or in pre-clinical model. Nevertheless, these inhibitors resulted in disappointing clinical trials. The resistance to TrkA inhibitors is in part due to the activation of alternative pathways through the formation of membrane receptor complexes. More precisely, my PhD work demonstrates that a particular form of the receptor CD44 interacts with TrkA leading to treatment resistance. Moreover, I also demonstrate an association between TrkA and two other receptors. I identified how these receptors interact and I developed some inhibitors targeting the interaction. These inhibitors could be effective for treating breast cancer. My PhD highlights the importance of membrane receptor complexes in cancer cells plasticity and their abilities to adapt for resisting to targeted therapies
Samba, Louaka Ascel Régis. "Détermination de la voie de signalisation cellulaire eucaryote détournée par la protéine bactérienne Cif". Toulouse 3, 2009. http://thesesups.ups-tlse.fr/614/.
Texto completoThe cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, that deregulate the host cell cycle. Upon injection into the host cell by pathogenic Escherichia coli, Cif inhibits G2/M transition via sustained inhibition of the mitosis inducer CDK1. I show that Cif induces not only G2 but also G1 cell cycle arrest depending on the stage of cells in the cell cycle during the infection. Those arrests were associated with stabilization of the cyclin-dependent kinase (CDK) inhibitors p21waf1 and p27kip1. CDKs complexes promote of the cell cycle transitions at both G1/S and G2/M. We recently demonstrated that functional Cif homologs are present in human pathogenic bacterial strains such as Burkholderia pseudomallei, Yersinia pseudotuberculosis, Photorhabdus asymbiotica and in symbiotic (for nematode) pathogenic (for insect) bacteria Photorhabdus luminescens. Those proteins, that share similar structures and catalytic sites, belong to the superfamily of enzymes including cystein proteases and acetyltransferases. Although the link between the activity and the cell cycle arrest remain to established, Cif proteins form a growing family of cyclomodulins that interact with very distinct hosts including insects, nematodes and humans. .
Loubidi, Mohammed. "Synthèse et réactivité de bicycles imidazo[1,2-a]imidazoles et imidazo[1,5- a]imidazoles à visée thérapeutique". Thesis, Orléans, 2017. http://www.theses.fr/2017ORLE2037.
Texto completoThe imidazo-imidazoles bicycles have received special attention among other nitrogen cycles due to their biologically interesting properties exploited in the medicine manufacturing. The imidazo-imidazole scaffold is one of the most representative nitrogen containing heterocycle, as it plays a significant role and possesses a major interest in drug synthesis and functionalization. In this work we report firstly a synthetic pathway to novel imidazo[1,2-a]imidazoles candidates for CKD inhibitors. Secondly we develop two strategies to prepareimidazo[1,5-a]imidazoles and their reactivity via pallado-catalyzed reactions. Finally, we disclose a fast and an efficient access to imidazo[1,5-a]imidazoles by using the Groebke-Blackburn-Bienaymé reaction (GBB), followed by a palladium catalysed intramolecular cyclization, affording thus new tetracyclic products with an elevated degree of molecular diversity
Courapied, Sandy. "Implication de l'oncogène STAT3 dans la réponse aux traitements de chimiothérapies : Application au cancer colorectal". Phd thesis, Université d'Angers, 2010. http://tel.archives-ouvertes.fr/tel-00576728.
Texto completoBriant, Rémi. "Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC". Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10256.
Texto completoSince the approval of imatinib (or Gleevec®), protein kinases have become major targets for the treatment of several pathologies (cancer, neurodegenerative diseases,…). Among the eight existing groups of protein kinases, the CMGC group consists of 61 serine-threonine kinases classified as CDKs (cyclin-dependent kinases), GSK3 (glycogen synthase kinases), CLKs (Cdc2-like kinases), DYRKs (dual specificity, tyrosine phosphorylationregulated kinases) or other sub-families. Nevertheless a major challenge remains concerning the development of kinase-modulating small molecules: the selectivity of these new inhibitors, which generally bind in the ATPbinding pocket, a common site for all protein kinases. Our team aims at synthesizing original and selective inhibitors of CMGC kinases. In this presentation, we are introducing the synthesis, the evaluation of the structure-activity relationships and the optimization of the selectivity of three series of heterocyclic inhibitors, targeting CMGC protein kinases. Based on N-&-N1 (GP0210), an inhibitor developed in the laboratory and currently in preclinical trials, the synthesis and the biological evaluation of a library of pyrazolo[1,5-a]triazines led to the identification of two series of compounds which inhibit CDK on the one hand and GSK3 on the other hand. From AT7519, a CDK and GSK3 inhibitor currently in phase II clinical trials in oncology, we synthesized new pyrazole-3-carboxamides, which are selective GSK3 inhibitors and may have different therapeutical applications. Finally we prepared derivatives of meriolines, CDK inhibitors that have been previously developed in our laboratory. These new compounds inhibit CLKs on the nanomolar scale and are selective against other CMGC kinases, especially against DYRKs. This last result has never been obtained so far
Perchey, Renaud. "Le rôle de p27Kip1 dans la mitose et dans l'instabilité génétique". Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30055.
Texto completoProgression through the cell cycle is regulated by the sequential activation of cyclin/CDK complexes. One level of regulation of these complexes is provided by their association with their inhibitors, the CKIs, which include p27Kip1 (p27). p27 is therefore an inhibitor of the cell division cycle, in this way, p27 acts as a tumor suppressor. However, in certain contexts, and especially when p27 is located in the cytoplasm, p27 has oncogenic functions. It appears that in addition to its role in the regulation of cyclin/CDK complexes, p27 has multiple CDK-independent roles and is involved in the control of various cellular processes such as migration, transcription, autophagy and cytokinesis. Determination of the interactome of p27 revealed that several proteins playing an essential role in cytokinesis could interact with p27, including PRC1 (Protein Regulating Cytokinesis 1) and Citron-Kinase (CitK). The objectives of my thesis are to understand how p27 participates in the control of cytokinesis via its interaction with these two proteins. Regulation of PRC1 activity by p27Kip1 PRC1 is necessary for the formation of the central spindle at the beginning of anaphase via its interaction with microtubules and other partners. For this project, my objectives were to confirm the p27/PRC1 interaction, to map the interaction domains on each partner, to test whether p27 could regulate PRC1 activity and determine by which mechanism, as well as the cellular consequences of this regulation. I validated the interactions in different cells models and identified the respective interaction domains. I found by a microtubule sedimentation technique in vitro that p27 prevents the interaction of PRC1 with microtubules. I was able to uncover two phenotypes. First, PRC1 overexpression induces excessive and massive microtubule bundling, which is abolished by co-expression of p27. Second, PRC1 overexpression causes binucleation and p27 co-expression prevents PRC1-induced binucleation. This phenotype is indicative of cytokinesis failure and suggests a CDK-independent role of p27 during cytokinesis. Citron-Kinase regulation by CDK1 and p27Kip1 Another p27 interactor previously reported by my team is CitK. CitK plays an essential role in cytokinesis and its depletion induces cytokinesis failure. CitK is involved in the final stages of cytokinesis (abscission), notably as a scaffold protein that bridges the plasma membrane and the contractile ring. The regulatory mechanisms of CitK remain poorly understood and it appears important to understand how this protein playing an essential role in cytokinesis is regulated. In our 2012 study, a p27CK- mutant, that cannot bind and inhibit cyclin-CDK complexes and is not degraded correctly by the proteasome, induced a phenotype of multinucleation by interfering with CitK activity, notably via the regulation of the CitK/RhoA interaction. We initially thought that the accumulation of p27CK- in G2/M drove this phenotype. However, our current data suggest that although the total amount of p27CK- is elevated, the amount of p27CK- at the midbody are similar to that of p27WT, suggesting that p27CK- lacks a feature that p27WT has. Since the only difference between p27WT and p27CK- is the ability to bind and inhibit cyclin/CDK complexes, we hypothesized that CitK can be regulated by CDK1 and that p27 participates in this regulation. My work has shown that CitK interacts with CDK1/Cyclin B1 in different cells lines
Bousquet, Laurence. "Etude comparative des thérapies anti-VIH : rôle des transporteurs d'efflux sur le passage transmembranaire des antirétroviraux au niveau des cellules CD4+ et de la barrière hémato-encéphalique". Phd thesis, Université Paris Sud - Paris XI, 2008. http://tel.archives-ouvertes.fr/tel-00364246.
Texto completoCertaines protéines d'efflux pourraient diminuer les concentrations intracellulaires d'IP. Ce travail étudie la pharmacocinétique intracellulaire des IP et leurs mécanismes de transfert à travers la membrane cellulaire à l'aide de modèles cellulaires.
Les IP pénètrent dans la cellule par diffusion passive et s'accumulent par fixation aux protéines cytosoliques.
Nous avons également étudié l'expression de la P-glycoprotéine à l'aide de cellules mononucléées du sang périphérique de patients infectés par le VIH et traités par des multithérapies antivirales à base d'IP.
Gloulou, Olfa. "Identification de nouvelles structures inhibitrices de kinases : conception synthèse et évaluation biologique". Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05P637/document.
Texto completoIn the introduction, the main functions of cyclin dependent kinases are detailed. Whenever it was possible the link with pathologies where these kinases are overexpressed is presented. This is followed by the description of the inhibitors which are actually undergoing clinical testing. Most of these clinical studies are targeting cancer and leukemia. Impressive clinical results have been disclosed for Dinaciclib, Palbociclib and Roscovitine. The synthesis of two series of compounds is then envisioned. The first series of products are purine derivatives bearing a hydroxybiarylmethyl group on the 6 position of the purine scaffold. Two approaches were compared in the synthesis of the hydroxylbiarylmethylamino group. In both approaches the key step was the orthoformylation of phenols using magnesium chloride as catalyst. The prepared compounds were evaluated against kinases and a tumor cell line. They were found more potent than homologous products without hydroxyls. The second families of products are thieno[3,2-d]pyrimidines. A new general route to these products based on the preparation of 7-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine which can allow the synthesis of a large diversity of trisubstituted derivatives
Zoubir, Mustapha. "Traitement anticancéreux et modulation du système immunitaire". Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T016.
Texto completoCancer therapies have made a gain widespread recognition in the reduction of tumor burden, patient survival and improved quality of life in a number of cancers. Unfortunately, these therapies exert an immunosuppressive effect by killing effectors or blocking the activity of certain biological factors involved in recruiting of the immune system. On the other hand, several studies have shown that these treatments could have the opposite effect by generating or promoting the induction of antitumor immune response, either by direct effect on the recruitment and activation of effectors immunity, either by potentiating cellular interactions by biological mechanisms. The latter involving cytokines, TLR stimulation, increased interactions between cells of the IS; which toggles between immunological anergy to a real system to eradicate cancer cells. In our laboratory, we tried to evaluate the involvement of the immune system in the therapeutic response induced by conventional cytotoxic agents. Here, we describe the effects of an inhibitor of cyclin kinases multi-target "CDKIs PHA-793887" tested in a phase I trial conducted at two sites in Europe. This unexpected finding is that 6 of 15 patients treated with this drug (PHA-793887) developed severe bacterial and viral infections and six of them showed reactivation of the herpes virus that has led us to study these effects on the immune system and in particular on the dialogue between dendritic (DCs) and natural killer (NK) cells. This work shows that this drug inhibits the signaling of toll-like receptor (TLR) thereby reducing the interaction DC / NK in vitro. Finally, stimulation of the cells of treated patients demonstrated a significant reduction of this signaling ex vivo. Thus, this immunosuppressive effect has an unexpected viral reactivation in 40% of patients. The second part of this work concerns the effects of metronomic dose of cyclophosphamide (CTX). The injection of a low dose in mice or metronomic dosing in humans, markedly promotes the differentiation of CD4+ T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells and promotes cell differentiation into Th17 lymphocytes (secreting interleukin-17 (IL-17)) and Th1 (secreting interferon-γ (IFN)). These were found in blood and in ascites carcinoma patients. Thus, CTX may participate in the generation of antitumor responses through Th 17 differentiation as was suggested by recent preclinical studies showing the existence of a correlation between the rate of Th17 lymphocytes infiltrating the tumor and tumor destruction
Crublet, Elodie. "Caractérisation de l'interaction entre la glycoprotéine d'enveloppe gp120 du VIH-1 et les héparanes sulfate : importance des changements conformationnels induits par la liaison à CD4". Phd thesis, 2008. http://tel.archives-ouvertes.fr/tel-00260979.
Texto completoTétreault, Pascal. "MMP-9/CD44 : un nouveau complexe ligand/récepteur impliqué dans la régulation de la fonction des cellules musculaires lisses bronchiques humaines". Thèse, 2008. http://hdl.handle.net/1866/7628.
Texto completoCalvo, Gonzalez Llilians. "Dissection moléculaire de la sénescence cellulaire induite par le stress et la thérapie dans le cancer de l’ovaire et son impact sur la réponse des patientes". Thèse, 2015. http://hdl.handle.net/1866/13853.
Texto completoHuman ovarian cancer (OvCa) is the deadliest gynecologic malignancy and existing surgical/chemotherapeutic treatment options have been relatively static for decades. We propose that understanding OvCa cell fate decisions taken in response to chemotherapy could guide new therapeutic opportunities. Damage-induced cellular senescence is often associated with TP53 activity, which is heavily mutated in high grade serous (HGS) OvCa (>90%), the most common form of this disease. Here, using patient derived tissues, we show that primary HGS-OvCa cultures predominantly trigger CDKN2A- associated (p16INK4A isoform) senescence following exposure to stress or chemotherapy. Key senescence hallmarks including altered morphology, senescence-associated-Betagalactosidase, DNA damage, cell cycle arrest and the senescence-associated secretory phenotype were evaluated and detected in damaged cells. Using tissue microarrays built from pre- and post-treatment human HGS-OvC tissue samples with accompanying clinical data, we quantified post-treatment hallmarks of senescence including reduced cell proliferation weeks after chemotherapy. Importantly, p16INK4A expression in pretreatment HGS-OvC samples correlated with increased patients survival, suggesting for the first time that senescence-competence in human cancer cells may have a beneficial impact on treatment outcomes for patients. In order to guide the potential improvement of existing human therapies via pharmacological senescence manipulation, our results suggests that it is important to determine for many types of human cancer whether treatment-induced senescence positively or negatively impacts disease progression and patient survival.