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.