Abemaciclib

Regulation of cell cycle is crucial in maintaining proper cell growth; dysregulated cell cycle signalling pathway is a key component in inducing hyperproliferation of cells and tumor formation in various cancers. G1 to S phase cell cycle progression, or transition through the G1 restriction point (R), is promoted by the retinoblastoma tumor suppressor protein (Rb)-mediated pathway. Activation of Rb-mediated pathway requires the interaction of Cyclin-dependent kinases (CDK) 4 and 6 with D-type cyclins, which drives the formation of active CDK4/CDK6 and subsequent phosphorylation of Rb.

Rb is a tumor suppressant protein that inhibits proliferation through binding to and suppressing the activity of the E2F family of transcription factors. However, phosphorylation of Rb relieves suppression of E2F to allow expression of genes required for passage through the restriction point. This leads to increased expression of downstream signalling molecules and activity of protein kinases that promote the cell cycle progression and initiation of DNA replication. Phosphorylation of Rb and other proteins by CDK4/6 additionally leads to transcription of genes involved in cell cycle-independent activities including signal transduction, DNA repair transcriptional control, and mRNA processing.

Abemaciclib selectively inhibits CDK4 and CDK6 with low nanomolar potency, inhibits Rb phosphorylation resulting in a G1 arrest and inhibition of proliferation, and its activity is specific for Rb-proficient cells. Unlike other CDK inhibitors such as DB09073 and DB11730, abemaciclib exhibits greater selectivity for CDK4 compared to CDK6.