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Fındık, Volkan. "Simulations atomistiques de la réaction d’acétylation d’amines et de l’inhibition covalente de l’enzyme Phosphoinositide 3-kinase (PI3K)". Electronic Thesis or Diss., Université de Lorraine, 2022. http://www.theses.fr/2022LORR0266.
Pełny tekst źródłaTargeted Covalent Inhibitors (TCIs) hold great promise for search of new drugs. They offer a number of potential advantages over traditional reversible inhibitors, such as extended residence time, increased potency, and the ability to make modifications for effective design. Kinase inhibitors are the most common examples of TCIs. Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets in oncology as they are involved in the signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Lysine (Lys) residues have gained increasing interest as an alternative for targeted covalent inhibition. Recently, the first selective and irreversible inhibitors with ester groups as electrophilic head targeting the Lys779 residue and covalently inactivating the PI3Kδ enzyme were reported. The main objective of this thesis is to elucidate the mechanism of the covalent inhibition of PI3Kδ by these ester inhibitors in order to assist future design of new inhibitors with superior activities. Prior to the mechanistic studies on the enzyme, initially, we performed ab initio and DFT calculations on the model reaction between methylamine and methyl, phenyl and p-NO2 phenyl acetates in aqueous solution. The same model systems were then studied by the "dual-level" QM/MM molecular dynamics approach. For the “low-level” option, PM3/TIP3P umbrella sampling QM/MM simulations were applied for the sampling. The obtained structures were then used to obtain perturbative corrections to the free energy with a “high-level” QM region at the M06-2X/6-311+G(d,p) level. The results show that thefirst step involves the formation of the zwitterionic tetrahedral intermediate. Then, for sufficiently electrophilic esters, such as the p-NO2 derivative, the reaction proceeds by dissociation of the zwitterion as an ion pair, followed by proton transfer leading to the formation of the expected products. We, then, employed similar computational tools to shed light on the mechanistic aspects of the enzyme. First, an active site model of the enzyme was built through classical molecular dynamics simulations. Then, ONIOM QM:QM approach at the M06-2X/6 -31+G(d,p):PM6 level was applied to get possible reaction mechanisms in this active site. These calculations guided us to refine the reaction mechanisms in enzyme environment which globally confirm the steps obtained from the small model system. We finally used this information to approach a dynamic QM/MM study on the enzyme using the same“dual-level” protocol established for the small model system, which allowed us to obtain the free energy profile of the inhibition mechanism of PI3Kδ for p-NO2 derivative of the ester inhibitor. The calculated barrier is in good agreement with the available experimental kinetic data, which validates the proposed theoretical approach and the obtained mechanisms. Through the elucidation of the inhibition mechanism of previously experimentally tested compounds, our study paves the way for the discovery of new inhibitors with improved activity with the help of theoretical chemistry tools
Touat, Mahdi. "Mécanismes et implications thérapeutiques de l'hypermutation dans les gliomes Mechanisms and Therapeutic Implications of Hypermutation in Gliomas Mismatch Repair Deficiency in High-Grade Meningioma: A Rare but Recurrent Event Associated With Dramatic Immune Activation and Clinical Response to PD-1 Blockade Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial Hyman DM. BRAF Inhibition in BRAFV600-Mutant Gliomas: Results From the VE-BASKET Study Glioblastoma Targeted Therapy: Updated Approaches From Recent Biology Successful Targeting of an ATG7-RAF1 Gene Fusion in Anaplastic Pleomorphic Xanthoastrocytoma With Leptomeningeal Dissemination Ivosidenib in IDH1-Mutated Advanced Glioma". Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL071.
Pełny tekst źródłaHigh tumor mutational burden (hypermutation) is observed in some gliomas; however, the mechanisms by which hypermutation develops and whether it predicts chemotherapy or immunotherapy response are poorly understood. Mechanistically, an association between hypermutation and mutations in the DNA mismatch-repair (MMR) genes has been reported in gliomas, but most MMR mutations observed in this context were not functionally characterized, and their role in causing hypermutation remains unclear. Furthermore, whether hypermutation enhances tumor immunogenicity and renders gliomas responsive to immune checkpoint blockade (e.g. PD-1 blockade) is not known. Here, we comprehensively analyze the clinical and molecular determinants of mutational burden and signatures in 10,294 gliomas, including 558 (5.4%) hypermutated tumors. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and MMR genes, and a more common, post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas recurring after temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas (COSMIC signature 11) was recapitulated by temozolomide-induced damage in MMR-deficient cells. While MMR deficiency was associated with acquired temozolomide resistance in glioma models, clinical and experimental evidence suggest that MMR-deficient cells retain sensitivity to the chloroethylating nitrosourea lomustine. MMR-deficient gliomas exhibited unique features including the lack of prominent T-cell infiltrates, extensive intratumoral heterogeneity, poor survival and low response rate to PD-1 blockade. Moreover, while microsatellite instability in MMR-deficient gliomas was not detected by bulk analyses, single-cell whole-genome sequencing of post-treatment hypermutated glioma cells demonstrated microsatellite mutations. Collectively, these results support a model where differences in the mutation landscape and antigen clonality of MMR-deficient gliomas relative to other MMR-deficient cancers may explain the lack of both immune recognition and response to PD-1 blockade in gliomas. Our data suggest a change in practice whereby tumor re-sequencing at relapse to identify progression and hypermutation could inform prognosis and guide therapeutic management
Riojas, Ramon Alberto. "Characterization of PDK1 regulation and function in the insulin-stimulated PI3-kinase pathway : a dissertation /". San Antonio : UTHSC, 2007. http://proquest.umi.com/pqdweb?did=1372010131&sid=1&Fmt=2&clientId=70986&RQT=309&VName=PQD.
Pełny tekst źródłaPiessen, Guillaume. "Rôles des mucines MUC1 et MUC4 dans l'adénocarcinome de l'oesophage : études in vitro, ex vivo et dans un modèle animal de carcinogenèse induite". Lille 2, 2007. http://www.theses.fr/2007LIL2S048.
Pełny tekst źródłaRajurkar, Mihir S. "GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation". eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/753.
Pełny tekst źródłaRajurkar, Mihir S. "GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation". eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/753.
Pełny tekst źródłaMarquette, Amélie. "Signalisation et oncogenèse dans le mélanome". Thesis, Paris Est, 2009. http://www.theses.fr/2009PEST0079.
Pełny tekst źródłaMelanoma, the most aggressive skin tumor, has become a major public health problem in many countries. Diagnosed early, it can be treated by surgical excision, but the prognosis for advanced melanoma is very poor because the tumor is resistant to all therapies used today. In order to develop new therapies to treat this tumor, we study the signaling pathways that play a major role in the proliferation, survival and differentiation of melanocytes and melanoma. These are the MAPK, PI3K pathway and the cyclic AMP (cAMP). We first demonstrated that some phosphodiesterases (PDEs; physiological inhibitors of cAMP pathway) are overexpressed in melanoma lines and thus inhibit the differentiation of these cells. Overexpression of PDEs is necessary for melanocyte transformation by oncogenic Ras when the reactivation of the cAMP pathway in melanoma lines inhibits their proliferation. These data suggest a therapeutic strategy that would aim to stimulate the differentiation of melanoma by reactivating the cAMP pathway could help to inhibit their proliferation. We have also shown that the protein kinase B-Raf, which is frequently mutated in melanoma, however, was inactivated in melanomas containing a mutation of Ras. We demonstrated that this inhibition was due to a downregulation of B-Raf by Erk substrate. Indeed, Erk phosphorylates B-Raf on its amino-terminal to prevent its interaction with Ras. This negative regulatory mechanism of B-Raf melanoma is forcing these lines to use isoform C-Raf. This work has implications for the treatment of melanoma. Indeed, if B-Raf is not used for the activation of MAPK in N-Ras mutated melanoma, the B-Raf inhibitors in clinical development will be ineffective in these cancers. We also demonstrated that a kinase inhibitor of B-Raf and C-Raf, which is in clinical development (Sorafenib), induces the activation of these kinases by heterodimerization in regulating their phosphorylation. These results reveal new mechanisms of regulation of proto-oncogene B-Raf and C-Raf, which could play an important role in the resistance of melanoma to Raf inhibitors, which are currently in clinical development