Cyclin-dependent kinase 2, Cyclin-dependent kinase 4, and Cyclin-dependent kinase 6 (CDK2/4/6)

Cyclin-dependent kinases 2, 4, and 6 (CDK2/4/6) are a group of serine/threonine protein kinases that play a fundamental role in regulating the mammalian cell cycle, specifically the transition from the G1 phase to the S phase [2, 5, 13]. CDK4 and CDK6 are typically activated by D-type cyclins in response to growth factors, where they initiate the phosphorylation of the retinoblastoma (Rb) protein [6, 10, 15]. CDK2 is subsequently activated by E-type cyclins to complete Rb phosphorylation, thereby releasing E2F transcription factors that trigger DNA synthesis [5, 6, 17]. Dysregulation of the CDK-Rb pathway is a hallmark of many cancers, leading to the uncontrolled proliferation of malignant cells [2, 4, 13]. While CDK4/6 inhibitors like palbociclib and ribociclib have transformed the treatment of hormone receptor-positive breast cancer, many patients eventually develop resistance [1, 3, 7]. This resistance is frequently mediated by the compensatory overactivation of CDK2, which allows the cell cycle to proceed independently of CDK4/6 [1, 4, 8, 18]. Consequently, next-generation inhibitors targeting CDK2, CDK4, and CDK6 simultaneously, such as PF-06873600, are being developed to overcome this resistance and improve clinical outcomes [1, 16, 18]. These drugs work by inducing cell cycle arrest and senescence in tumor cells, though they are associated with side effects such as neutropenia and gastrointestinal distress [1, 14].

Other names

Cell division protein kinase 2Cell division protein kinase 4Cell division protein kinase 6CDK2CDK4CDK6p33(CDK2)PSK-J3PLSTIRE

Inhibition of CDK2, CDK4, and CDK6 prevents the phosphorylation of the retinoblastoma (Rb) protein, thereby blocking the release of E2F transcription factors and arresting the cell cycle at the G1/S transition [1, 10, 12, 14]. This leads to the induction of cytostasis, senescence, and apoptosis in sensitive tumor cells [14, 15].