cdk inhibitors as new targets for cancer treatment
TRANSCRIPT
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Cyclin – dependent Kinases as new targets for cancer treatment.
Cian D’ArcySachin Kumar SinghSaraswathi Rajakumar
November 2nd 2016
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Overview
Cyclin dependent kinase and cyclin
Cell cycle clock and Cyclin – dependent kinase
CDK-cyclin complex mechanism
CDK4/6 inhibitors as anticancer drugs
Current Research
Conclusion
References
CDK – Cyclin Dependent Kinases
Rb - Retinoblatoma
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Cyclin-dependent Kinases and cyclins
CDK is an inactive catalytic subunit of a serine/threonine kinase
Cyclins are regulatory subunits
Cyclin and CDK forms complex that regulates cell cycle
Image Source:https://cellbiology.med.unsw.edu.au
Cell proliferation is controlled by Cell cycle
Cancer cells have high cell proliferation
Therefore, by inhibiting CDK complex activity we can arrest cell proliferation.
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Cell cycle clock and Cyclin Dependent Kinase
Check points monitors the cell cycle process
CDK is depended on Cyclin and forms cyclin-CDK complex
CDK level is always stable
Respective Cyclins are produced and degraded ones the next step arrives
G1 is a decision making point
Thus CDK4 and CDK6 are targets for anticancer drugs.
Image source: Weinberg, R., 2013
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CDK4/6 forms complex with cyclin D
CDK4/6 complex phosphorylates Retinoblastoma protein
Release of E2F and DP transcription factors.
Transition into S phase
Endogenous CDK inhibitors control further proliferation
Cyclin-CDK4/6 mechanism
Image Source: Sanchez-Martinez et al., 2015.
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CDK4/6 inhibitors
Inhibitors target the formation of CDK4/6 Complex
Prevents Rb phosphorylation
Induces G1 cell cycle arrest
Most drugs under clinical trails are kinase inhibitors
Palbociclib, abemaciclib, ribociclib advanced to Phase III trials
Rb phoporylation by CDK4/6 inhibition and induced G1 cell cycle arrest
FDA approved use of Palbociclib in february 2015 for metastatic breast cancer
Image Source: Vidhula & Rugo., 2016
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ATP competitive CDK inhibitors
Substrate competitive protein kinase inhibitors
Cyclin-CDK binding is tight
Chimeric proteins that target protein-protein interactions (MM-D37K)
Peptidomimetic molecule that mimics endogenous CDK inhibitors
Current drugs and research
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Conclusion
Cell proliferation is controlled by cell cycle
Cell cycle is regulated by cyclin – CDK complex.
By inhibiting the activity of cyclin dependent kinase, cell proliferation in cancer cells can be arrested.
Most CDK inhibitors under study are with modest toxicity and are oral therapy.
Targeted therapy by selective inhibition of CDK along with other therapies could soon be an ultimate treatment plan.
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References
Vidula, N. and Rugo, H.S., 2016. Cyclin-dependent kinase 4/6 inhibitors for the treatment of breast cancer: a review of preclinical and clinical data. Clinical breast cancer, 16(1), pp.8-17.
Sánchez-Martínez, C., Gelbert, L.M., Lallena, M.J. and de Dios, A., 2015. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorganic & medicinal chemistry letters, 25(17), pp.3420-3435.
Weinberg, R., 2013. The biology of cancer. Garland science.
Finn, Richard S., et al. "The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study." The lancet oncology 16.1 (2015): 25-35.
https://cellbiology.med.unsw.edu.au
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Questions and Discussion
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