Cyclin – dependent Kinases as new targets for cancer treatment.

Cian D’ArcySachin Kumar SinghSaraswathi Rajakumar

November 2nd 2016

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

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.

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

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.

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

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

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.

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

Questions and Discussion

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