Mechanism of Action Magnifier – 2016 Desk Reference

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Abemaciclib (LY2835219): a Dual Inhibitor of CDK4 and CDK6

Cyclin-dependent kinases (CDKs) 4 and 6 are overactive in many human cancers, resulting in a loss of regulation of the G1 cell cycle restriction point and making malignant cells less responsive to normal growth controls.1,2

CDK4 and CDK6


CDKs are key regulators of cell proliferation.3 In many tumor types, CDK4 and CDK6 are activated through mutation, overexpression of D-type cyclins, or loss of inhibitory protein (eg, p16, p21).4 In a complex with D-type cyclins, CDK4 and CDK6 phosphorylate and inactivate the retinoblastoma tumor suppressor protein, which enables E2F proteins to facilitate G1 to S-phase cell cycle progression.3,4 Thus, abnormal activation of CDK4 or CDK6 in cancer cells can confer a growth advantage.5

Reestablishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy.6

Abemaciclib

Abemaciclib is designed to be a small molecule inhibitor of both CDK4 and CDK6.7 Abemaciclib has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 and CDK6 that inhibits phosphorylation and prevents inactivation of the retinoblastoma tumor suppressor protein, thereby inducing G1 cell cycle arrest and constraining cancer cell proliferation.5,7,8

Abemaciclib is currently being investigated in clinical trials for the treatment of a number of different cancers, including breast cancer, non–small cell lung cancer, metastatic melanoma, and mantle cell lymphoma.

References

  1. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24:1770-1783.
  2. Ibrahim N, Haluska FG. Molecular pathogenesis of cutaneous melanocytic neoplasms. Annu Rev Pathol. 2009;4:551-579.
  3. Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene. 2014;33:1890-1903.
  4. Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009;220:292-296.
  5. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32:825-837.
  6. Mayer EL. Targeting breast cancer with CDK inhibitors. Curr Oncol Rep. 2015;17:443.
  7. Sánchez-Martínez C, Gelbert LM, Lallena MJ, et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg Med Chem Lett. 2015;25:3420-3435.
  8. Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res. 2014;20:3379-3383.
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