(A) A schema of the mammalian cell cycle. When released from Rb after it is phosphorylated by cyclin D1–CDK4, E2F1 directly activates the transcription of CCNA2 (encoding cyclin A), TK1 (encoding thymidine kinase), PCNA (encoding proliferating cell nuclear antigen), CDK1 (encoding cyclin-dependent kinase I), and EZH2 (encoding EZH2), among other target genes. (B) Three oral small molecule reversible CDK4/6 inhibitors.