Log in

Relevant bibliographies by topics / Cdk4/6 Inhibition

Contents

Journal articles
Dissertations / Theses
Book chapters
Conference papers

Academic literature on the topic 'Cdk4/6 Inhibition'

Author: Grafiati

Published: 25 June 2021

Last updated: 7 February 2022

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles

Select a source type:

Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'Cdk4/6 Inhibition.'

Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.

You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.

Journal articles on the topic "Cdk4/6 Inhibition"

1

Lu, Shuyan, Tae Sung, Marina Amaro, Brad Hirakawa, Bart Jessen, and Wenyue Hu. "Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells." Toxicological Sciences 177, no. 1 (June 18, 2020): 226–34. http://dx.doi.org/10.1093/toxsci/kfaa092.

Full text

Abstract:

Abstract Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. In addition, collateral damage to highly proliferative normal cells by CDK inhibitors remains a safety concern. Intestinal epithelial cells are highly proliferative and the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. Using the rat intestinal epithelial (IEC6) cells as an in vitro model, we found that the selective CDK4/6 inhibitor palbociclib lacked potent anti-proliferative activity in IEC6 relative to the breast cancer cell line MCF7, indicating the absence of intestinal cell reliance on CDK4/6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, we chose common targets of CDK inhibitors (CDK 1, 2, 4, 6, and 9) for targeted gene knockdown to evaluate phenotypes. Surprisingly, only CDK1 and CDK9 knockdown demonstrated profound cell death or had moderate growth effects, respectively. CDK2, 4, or 6 knockdowns, whether single, double, or triple combinations, did not have substantial impact. Studies evaluating CDK1 knockdown under various cell seeding densities indicate direct effects on viability independent of proliferation state and imply a potential noncanonical role for CDK1 in intestinal epithelial biology. This research supports the concept that CDK1 and CDK9, but not CDKs 2, 4, or 6, are essential for intestinal cell cycle progression and provides safety confidence for interphase CDK inhibition.

APA, Harvard, Vancouver, ISO, and other styles

2

Shapiro, Geoffrey I. "Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment." Journal of Clinical Oncology 24, no. 11 (April 20, 2006): 1770–83. http://dx.doi.org/10.1200/jco.2005.03.7689.

Full text

Abstract:

Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor–dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B–responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.

APA, Harvard, Vancouver, ISO, and other styles

3

Fassl, Anne, Christopher Brain, Monther Abu-Remaileh, Iga Stukan, Deborah Butter, Piotr Stepien, Avery S. Feit, et al. "Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition." Science Advances 6, no. 25 (June 2020): eabb2210. http://dx.doi.org/10.1126/sciadv.abb2210.

Full text

Abstract:

Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

APA, Harvard, Vancouver, ISO, and other styles

4

Baughn, Linda B., Maurizio Di Liberto, Kaida Wu, Peter Toogood, Tracey Louie, Rachel Gottschalk, Ruben Niesvizky, et al. "A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cdk4/6." Blood 108, no. 11 (November 16, 2006): 369. http://dx.doi.org/10.1182/blood.v108.11.369.369.

Full text

Abstract:

Abstract Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow (BM). Inhibition of Cdk4 and Cdk6 by the Cdk inhibitor, p18(INK4c), is required for the generation of normal, functional plasma cells1. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of Cdk4-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of BM myeloma cells in vivo2. These data identify Cdk4 and Cdk6 as key determinants in the loss of cell cycle control in myeloma and suggest that Cdk4/6 may be effective targets for therapeutic intervention. Here we show that by specific inhibition of Cdk4/6, the orally active small molecule PD 0332991 potently induces G1 arrest in primary BM myeloma cells ex vivo, and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation, and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B cell cancers.

APA, Harvard, Vancouver, ISO, and other styles

5

Vilgelm, Anna E., Nabil Saleh, Rebecca Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C. Andrew Johnson, et al. "MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21." Science Translational Medicine 11, no. 505 (August 14, 2019): eaav7171. http://dx.doi.org/10.1126/scitranslmed.aav7171.

Full text

Abstract:

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.

APA, Harvard, Vancouver, ISO, and other styles

6

Facharztmagazine, Redaktion. "Brustkrebs: CDK4/6-Inhibition punktet." Im Fokus Onkologie 23, no. 4 (September 2020): 97. http://dx.doi.org/10.1007/s15015-020-2542-8.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Facharztmagazine, Redaktion. "CDK4/6 -Inhibition bei Brustkrebs." Im Fokus Onkologie 24, no. 3 (June 2021): 73. http://dx.doi.org/10.1007/s15015-021-3516-1.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Facharztmagazine, Redaktion. "CDK4/6 -Inhibition bei Brustkrebs." InFo Hämatologie + Onkologie 24, no. 6 (June 2021): 68. http://dx.doi.org/10.1007/s15004-021-8712-9.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

De Dominici, Marco, Patrizia Porazzi, Youcai Xiao, Allen Chao, Hsin-Yao Tang, Gaurav Kumar, Paolo Fortina, et al. "Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs." Blood 135, no. 18 (April 30, 2020): 1560–73. http://dx.doi.org/10.1182/blood.2019003604.

Full text

Abstract:

Abstract Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6–targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or tyrosine kinase inhibitor–resistant primary Ph+ ALL cells, and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib. These studies provide “proof of principle” that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the “CDK6 dependence” of Ph+ ALL and, perhaps, of other hematologic malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors.

APA, Harvard, Vancouver, ISO, and other styles

10

DiRocco, Derek P., John Bisi, Patrick Roberts, Jay Strum, Kwok-Kin Wong, Norman Sharpless, and Benjamin D. Humphreys. "CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury." American Journal of Physiology-Renal Physiology 306, no. 4 (February 15, 2014): F379—F388. http://dx.doi.org/10.1152/ajprenal.00475.2013.

Full text

Abstract:

Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or “pharmacological quiescence,” represents a novel strategy to prevent AKI.

APA, Harvard, Vancouver, ISO, and other styles

More sources

Dissertations / Theses on the topic "Cdk4/6 Inhibition"

1

Nakatani, Kana. "Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263584.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Knudsen, Erik S., and Agnieszka K. Witkiewicz. "Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer." IMPACT JOURNALS LLC, 2014. http://hdl.handle.net/10150/622114.

Full text

Abstract:

ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen. Chronic treatment with CDK4/6 inhibitors results in the consistent suppression of genes involved in cell cycle, while eliciting the induction of a comparable number of genes involved in multiple processes. The CDK4/6 inhibitor treatment shifted ER+/HER2- models from a high risk (luminal B) to a low risk (luminal A) molecular-phenotype using established gene expression panels. Consonantly, genes repressed by CDK4/6 inhibition are strongly associated with clinical prognosis in ER+/HER2- cases. This gene repression program was conserved in an aggressive triple negative breast cancer xenograft, indicating that this is a common feature of CDK4/6 inhibition. Interestingly, the genes upregulated as a consequence of CDK4/6 inhibition were more variable, but associated with improved outcome in ER+/HER2- clinical cases, indicating dual and heretofore unknown consequence of CDK4/6 inhibition. Interestingly, CDK4/6 inhibition was also associated with the induction of a collection of genes associated with cell growth; but unlike suppression of cell cycle genes this signaling was antagonized by endocrine therapy. Consistent with the stimulation of a mitogenic pathway, cell size and metabolism were induced with CDK4/6 inhibition but ameliorated with endocrine therapy. Together, the data herein support the basis for profound interaction between CDK4/6 inhibitors and endocrine therapy by cooperating for the suppression of cell cycle progression and limiting compensatory pro-growth processes that could contribute to therapeutic failure.

APA, Harvard, Vancouver, ISO, and other styles

3

He, Wei. "Mathematical Modeling of Therapies for MCF7 Breast Cancer Cells." Diss., Virginia Tech, 2021. http://hdl.handle.net/10919/103967.

Full text

Abstract:

Estrogen receptor (ER)-positive breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of any targeted therapy often results in resistance to the therapy. Our ultimate goal is to use mathematical modelling to optimize alternating therapies that not only decrease proliferation but also stave off resistance. Toward this end, we measured levels of key proteins and proliferation over a 7-day time course in ER-positive MCF7 breast cancer cells. Treatments included endocrine therapy, either estrogen deprivation, which mimics the effects of an aromatase inhibitor, or fulvestrant, an ER degrader. These data were used to calibrate a mathematical model based on key interactions between ER signaling and the cell cycle. We show that the calibrated model is capable of predicting the combination treatment of fulvestrant and estrogen deprivation. Further, we show that we can add a new drug, palbociclib, to the model by measuring only two key proteins, c-Myc and hyperphosphorylated RB1, and adjusting only parameters associated with the drug. The model is then able to predict the combination treatment of estrogen deprivation and palbociclib. Then we added the dynamics of estrogen concentration in the medium into the model and extended the short-term model to a long-term model. The long-term model can simulate various mono- or combination treatments at different doses over 28 days. In addition to palbociclib, we add another Cdk4/6 inhibitor to the model, abemaciclib, which can induce apoptosis at high concentrations. Then the model can match the effects of abemaciclib treatment at two different doses and also capture the apoptosis effects induced by abemaciclib. After calibrating the model to these different treatment conditions, we used the model to explore the synergism among these different treatments. The mathematical model predicts a significant synergism between palbociclib or abemaciclib in combination with fulvestrant. And the predicted synergisms are verified by experiments. This critical synergism between these Cdk4/6 inhibitors and endocrine therapy could reflect the reason that Cdk4/6 inhibitors achieve pronounced success in clinic trails. Lastly, we used protein biomarkers (cyclinD1, cyclinE1, Cdk4, Cdk6 and Cdk2) and palbociclib dose-response proliferation assays to assess the difference between mono- and alternating therapy after 10 weeks of treatments. But neither the protein levels nor palbociclib dose-response show significant differences after 10 weeks of treatment. Therefore, we cannot conclude that alternating therapy delays palbociclib resistance compared with palbociclib mono-treatment after 10 weeks. Longer term experiments or other methods will be needed to uncover any difference. However, in this research we showed that a mechanism-based mathematical model is able to simulate and predict various effects of clinically-used treatments on ER-positive breast cancer cells at different time scales. And this mathematical model has the potential to explore ideas for potential drug treatments, optimize protocols that limit proliferation, and determine the drugs, doses, and alternating schedule for long term experiments.
Doctor of Philosophy
Estrogen receptors are proteins found inside breast cancer cells that are activated by the hormone estrogen. Estrogen-receptor positive breast cancer is the most common type of breast cancer and accounts for about 70% of breast cancer tumors. Endocrine therapy, which inhibits estrogen receptor signaling, and Cyclin-dependent kinase 4 and 6 (Cdk4/6) inhibitors are the preferred first-line therapy for patients with estrogen receptor-positive cancers. We built a mathematical model of MCF7 cells (an estrogen receptor-positive breast cancer cell line) in response to these standard first-line therapies. This mathematical model can capture the experimentally observed protein and cell proliferation changes in response to various treatment conditions, including different drug combinations, different doses, and different treatment durations up to 28 days. The model can then be used to look for more effective treatment possibilities. In particular, our mathematical model predicted a strong synergism between Cdk4/6 inhibitors and endocrine therapy, which could allow significant reductions in drug dosage while producing the same effect. This synergism was verified by experiments. In addition to treatment methods where one drug or combination of several drugs is used continuously, we consider alternating among various therapies in a fixed cycle. The mathematical model can help us determine which drugs and which doses might be most appropriate. Since an alternating therapy doesn't inhibit one particular target non-stop, the hope is that alternating therapies can delay the onset of drug resistance, where the drug becomes less effective or stops working completely. Unfortunately, an initial 10- week experiment to test for differences in resistance to a mono-therapy versus an alternating therapy did not show a significant difference, pointing to the need for longer experiments to see if alternating therapies can actually make a difference in resistance. Mathematical models will be important for determining the drugs, doses, and time intervals to be used in these experiments, as figuring out the best options by trial and error in such long-term experiments is not practical.

APA, Harvard, Vancouver, ISO, and other styles

4

Pan, Qi [Verfasser], Jürgen E. [Akademischer Betreuer] Gschwend, Roland M. [Gutachter] Schmid, and Jürgen E. [Gutachter] Gschwend. "Identification of molecular mechanisms induced by CDK4/6 inhibition / Qi Pan ; Gutachter: Roland M. Schmid, Jürgen E. Gschwend ; Betreuer: Jürgen E. Gschwend." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1172880123/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Tong, Zhichao [Verfasser], Jürgen E. [Akademischer Betreuer] Gschwend, Jürgen E. [Gutachter] Gschwend, and Dieter [Gutachter] Saur. "Functional genomics identifies multiple clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer / Zhichao Tong ; Gutachter: Jürgen E. Gschwend, Dieter Saur ; Betreuer: Jürgen E. Gschwend." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1189815451/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Furnish, Robin. "Evaluating Immune Modulatory Therapeutic Strategies for Diffuse Intrinsic Pontine Glioma." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849080346532.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

Ebner, Benedikt [Verfasser]. "Kombinationstherapien mit dem CDK4/6 Inhibitor Palbociclib und weiteren Target-Therapeutika im Urothelkarzinom / Benedikt Ebner." München : Verlag Dr. Hut, 2021. http://d-nb.info/1238422977/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Fischer, Luca [Verfasser], and Martin [Akademischer Betreuer] Dreyling. "Zielgerichtete Therapien beim Mantelzelllymphom : Der neue CDK4/6-Inhibitor Abemaciclib in Mono- und Kombinationstherapie / Luca Fischer ; Betreuer: Martin Dreyling." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1190033135/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Köhler, Lena. "Radiotracer für die molekulare Bildgebung: Radiomarkierung von Inhibitoren der CDK4/6 mit den Radionukliden Iod-124 und Fluor-18." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2010. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-38369.

Full text

Abstract:

Krebserkrankungen stellen in Deutschland die zweithäufigste Todesursache dar und die Anzahl der Neuerkrankungen nimmt stetig zu. Frühzeitige Diagnosen und Therapiemöglichkeiten sind daher dringend erforderlich. Cyklinabhängige Proteinkinasen (Cdk) spielen eine entscheidende Rolle bei der Regulation des Zellzyklus. Viele Tumore zeigen eine deregulierte Cdk4‑Aktivität und/oder ‑Expression. Insgesamt zeigen ca. 80% aller Tumore eine Fehlregulation der für den Zellzyklus zentralen Cdk4/CykD1/INK4/pRb/E2F Signalkaskade. Somit besitzen Cdks ein enormes therapeutisches Potential im Kampf gegen Krebs. Die spezifische Inhibierung der Cdks verhindert die Zellproliferation und damit das Tumorwachstum. In den letzten Jahren wurden verschiedenste Strukturklassen vorgestellt, die als Cdk4-Inhibitor wirken. Im Rahmen der Promotion sollen die Möglichkeiten einer funktionellen Tumordiagnose mittels cyklinabhängiger Kinasen untersucht werden. Die Entwicklung von radioaktiv markierten Inhibitoren der Cdk4/6 als Radiotracer und ihre radiopharmakologische Charakterisierung stellt dabei einen neuen Ansatz dar. Um die Rolle der Cdk4/6 im Zellzyklus von gesunden und deregulierten (z.B. Tumor-) Zellen aufzuklären, sollten mit Iod-124 und Fluor-18 markierte Inhibitoren eingesetzt werden, die hochselektiv diese Cdks blockieren. Zunächst wurden verschiedene Inhibitoren der Cdk4/6 und deren Vorstufen für die Radiomarkierung dargestellt. Die bereits aus den Vorarbeiten von VanderWel et al., 2005 und Toogood et al., 2001 bekannten Syntheserouten mussten dazu optimiert werden und für neue Verbindungen, wie die fluorethylierten Substanzen, wurden neue Reaktionswege gefunden. Die dargestellten Referenzverbindungen CKIA-E wurden anschließend mittels Durchflusszytometrie an den Zelllinien HT-29 und FaDu auf ihre inhibitorischen Wirkung untersucht. Die Untersuchungen der Verbindungen CKIA/B/E zeigte, dass ein Zellzyklusarrest unter Einwirkung der Inhibitoren erreichbar ist. Die weiteren Untersuchungen zur Radiomarkierbarkeit sowie die radiopharmakologische Evaluation sollten daher an den Verbindungen CKIA, CKIB und CKIE stattfinden. Die Darstellung der Verbindungen [124I]CKIA und [124I]CKIB erfolgte in zwei Schritten über die elektrophile Substitution durch regioselektive Destannylierung mit anschließender Entschützung der Seitenkette. Die Darstellung der fluorethylierten Verbindung erfolgte ebenfalls über eine Zweischrittsynthese beginnend mit der Synthese der prosthetischen Gruppe [18F]BFE aus der Tosylmarkierungsvorstufe. Die zur Markierung des sekundären Amins zur Auswahl stehenden prosthetischen Gruppen [18F]Fluorethyltosylat ([18F]FETos) und [18F]Bromfluorethan ([18F]BFE) wurden auf ihre Eignung untersucht, ebenso wie die Auswahl einer geeigneten Markierungsvorstufe für die Darstellung der prosthetischen Gruppe. Die optimierten Syntheserouten ermöglichten die Isolierung von ausreichenden Mengen an Produktaktivität für die radiopharmakologischen Untersuchungen. Es fanden, neben der Bestimmung der spezifischen Aktivität und der Lipophilie der Verbindungen, Zellaufnahmeuntersuchungen und Bestimmungen zur Stabilität der Verbindungen in vitro, ex vivo und in vivo statt. Die radioiodierten Verbindungen konnten des Weiteren zur Untersuchungen der Bioverteilung in normalen männlichen Wistar-Ratten eingesetzt werden. Für alle drei Verbindungen konnte eine sehr hohe in vitro-Stabilität festgestellt werden. Die Zellaufnahmeuntersuchungen zeigten vor allem für die Verbindungen [124I]CKIA und [124I]CKIB eine beträchtliche Zellaufnahme von über 1000% ID/mg Protein nach 2 h. Die Zellaufnahme der Verbindung CKIE ist geringer, sollte allerdings für eine in vivo-Anwendung ausreichend sein. Die Untersuchung der in vivo‑Stabilität der Verbindungen [124I]CKIA, [124I]CKIB und [18F]CKIE im Blut von Wistar Ratten ergab allerdings, dass alle Verbindungen schnell metabolisiert werden. Die Untersuchung der Bioverteilung der radioiodierten Verbindungen belegen eine in vivo Radiodeiodierung sowie eine hohe hepatobliliäre Auscheidungsrate. Im Hinblick auf eine Anwendung als Radiotracer konnten im Rahmen dieser Arbeit neue Erkenntnisse gewonnen werden. Die dargestellten Inhibitoren sind in der Lage am Zellmodell den Zellzyklusarrest in der G1-Phase zu induzieren. Eine Radiomarkierung der ausgewählten Strukturen liefert das Produkt mit reproduzierbarer Ausbeute in hoher radiochemischer Reinheit und ausreichender spezifischer Aktivität, allerdings ist eine Herstellung der fluorethylierten Verbindung unter GMP-Bedingungen nur schwer realisierbar. Die radiomarkierten Verbindungen zeigen eine hohe in vitro-Stabilität und werden energieabhängig in die Zelle aufgenommen. Anhand der Stabilitätsuntersuchungen in vivo wurde gezeigt, dass alle drei Verbindungen in vivo instabil sind und sehr schnell hepatobiliär eliminiert.

APA, Harvard, Vancouver, ISO, and other styles

10

Heimer, Maurice Maximilian [Verfasser], and Clemens [Akademischer Betreuer] Cyran. "18F-FDG-PET/CT und diffusionsgewichtete MRT zum Monitoring einer BRAF- und CDK4/6-Inhibitor Kombinationstherapie im murinen Modell eines humanen Melanoms / Maurice Maximilian Heimer ; Betreuer: Clemens Cyran." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1206877987/34.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Book chapters on the topic "Cdk4/6 Inhibition"

1

Toogood, Peter L., and Nathan D. Ide. "Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer." In Innovative Drug Synthesis, 167–96. Hoboken, NJ, USA: John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118819951.ch9.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Taber, Douglass. "Complex Cyclic Ethers: (+)-Conocarpan (Hashimoto), (-)-Brevisamide (Satake/ Tachibana), (+)-Bruguierol A (Fañanás/ Rodríguez), (-)-Berkelic Acid (Snider), and (-)-Aigialomycin D (Harvey)." In Organic Synthesis. Oxford University Press, 2011. http://dx.doi.org/10.1093/oso/9780199764549.003.0052.

Full text

Abstract:

( + )-Conocarpan 3, isolated from the wood of Conocarpus erectus , exhibits insecticidal, antifungal and antitrypanosomal activity. Shunichi Hashimoto of Hokkaido University developed (J. Org. Chem. 2009, 74 , 4418) a chiral Rh (II) carboxylate that effected the cyclization of 1 to 2, setting the absolute configuration of 3. The dinoflagellate Karenia brevis produces the brevetoxins, a family of complex polyethers. Recently, the first N-containing cyclic ether, (-)-Brevisamide 6, was isolated from K. brevis . Masayuki Satake and Kazuo Tachibana of the University of Tokyo, in their synthesis of 6 (Organic Lett. 2009, 11, 217) found it convenient to set the relative configuration around the six-membered ring by double hydroboration/oxidation of the diene 4. ( + )-Bruguierol A 9, isolated from the mangrove Bruguiera gymmorrhiza, has an unusual bridged structure. Francisco J. Fañanás and Félix Rodríguez of the Universidad de Oviedo conceived (J. Org. Chem. 2009, 74, 932) an elegant approach to the construction of 9, based on the Pt-mediated addition of the alcohol of 7 to the alkyne to give a transient enol ether. It is not clear whether the subsequent intramolecular electrophilic addition to the aromatic ring is mediated by the Pt, or by a trace of adventitious acid. The overall transformation was remarkably efficient. The Berkeley Pit in Butte, Montana, is an abandoned open-pit copper mine filled with 30 billion gallons of pH = 2.5 water heavily contaminated with, inter alia , copper, cadmium, arsenic and zinc. Remarkably, microorganisms can be cultured from that water. (-)-Berkelic Acid 13 , isolated from a Penicillium fungus, showed selective activity against OVCAR-3 ovarian cancer. Barry B. Snider of Brandeis University set (Angew. Chem. Int. Ed. 2009, 48, 1283) the absolute configuration of the central five-membered ring ether of 13 by conjugate addition of the enantiomerically-pure reagent 11 to the prochiral lactone 10. (-)-Aigialomycin D 17, isolated from the mangrove fungus Aigialus parvus , was found to be a selective inhibitor of the kinases CDK1, CDK5 and GSK3.

APA, Harvard, Vancouver, ISO, and other styles

Conference papers on the topic "Cdk4/6 Inhibition"

1

Zhang, Yixiang, Ewa Sicinska, Samuel Moss, Jeffrey T. Czaplinski, Yuchuan Wang, Christopher Brain, George D. Demetri, Sunkyu Kim, Andrew L. Kung, and Andrew J. Wagner. "Abstract A236: Human liposarcoma growth inhibition by novel CDK4/6 inhibitor LEE011." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-a236.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Olanich, Mary E., Wenyue Sun, Stephen M. Hewitt, Zied Abdullaev, Svetlana D. Pack, and Frederic G. Barr. "Abstract 3093: CDK4 amplification reduces sensitivity to CDK4/6 inhibition in fusion-positive rhabdomyosarcoma." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-3093.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

Pandey, Kamal. "Abstract 5811: Combined inhibition of CDK2 and CDK4/6 overcomes acquired resistance to CDK4/6 inhibitors in breast cancer via RB-independent pathway." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5811.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Hall, Claire R., John E. Bisi, and Jay C. Strum. "Abstract 4414: Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-4414.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Hall, Claire R., John E. Bisi, and Jay C. Strum. "Abstract 4414: Inhibition of CDK2 overcomes primary and acquired resistance to CDK4/6 inhibitors." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4414.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Witzleben, A., L. Goerttler, R. Marienfeld, H. Barth, K. Mellert, P. Möller, S. Brüderlein, TK Hoffmann, and TFE Barth. "Charakterisierung von Chordom Zelllinien und Inhibition des CDK4/6 Signalwegs." In Abstract- und Posterband – 89. Jahresversammlung der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie e.V., Bonn – Forschung heute – Zukunft morgen. Georg Thieme Verlag KG, 2018. http://dx.doi.org/10.1055/s-0038-1640188.

Full text

APA, Harvard, Vancouver, ISO, and other styles

7

DeCristo, Molly J., Shom Goel, April C. Watt, Haley BrinJones, Jaclyn Sceneay, Ben B. Li, Naveed Khan, et al. "Abstract B04: CDK4/6 inhibition triggers an antitumor immune response." In Abstracts: AACR Special Conference on Tumor Immunology and Immunotherapy; October 1-4, 2017; Boston, MA. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/2326-6074.tumimm17-b04.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Barghi, Farinaz, Pankita H. Pandya, M. Reza Saadatzadeh, Khadijeh Bijangi-Vishehsaraei, Barbara J. Bailey, Erika A. Dobrota, Courtney Young, et al. "Abstract 3043: Targeting CDK4/6 inhibitor resistance in relapsed osteosarcoma via PI3 Kinase inhibition." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-3043.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Iyengar, Mangala, Lan Coffman, and Ronald Buckanovich. "Abstract A73: CDK4/6 inhibition as maintenance therapy in ovarian cancer." In Abstracts: AACR Special Conference: Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; October 17-20, 2015; Orlando, FL. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1557-3265.ovca15-a73.

Full text

APA, Harvard, Vancouver, ISO, and other styles

10

Jeselsohn, R. "Abstract MS2-2: Targeting the cell cycle - Beyond CDK4/6 inhibition." In Abstracts: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.sabcs19-ms2-2.

Full text

APA, Harvard, Vancouver, ISO, and other styles

We offer discounts on all premium plans for authors whose works are included in thematic literature selections. Contact us to get a unique promo code!