Cyclin-dependent kinase 4 (CDK4) (CDK4)

Cyclin-dependent kinase 4 (CDK4) is a pivotal serine/threonine protein kinase that functions as the catalytic subunit of the CDK4-cyclin D complex, which serves as a master regulator of the G1-to-S phase transition in the mammalian cell cycle [1, 6]. In response to mitogenic signaling, CDK4 associates with D-type cyclins to phosphorylate the retinoblastoma (Rb) protein, a process that relieves the inhibition of E2F transcription factors and enables the expression of genes required for DNA replication and cell proliferation [5, 12]. Dysregulation of the CDK4 pathway—frequently occurring through gene amplification, cyclin D overexpression, or the loss of the endogenous inhibitor p16INK4A—is a hallmark of many human malignancies, including breast cancer and melanoma [3, 4, 13]. Consequently, the development of selective CDK4/6 inhibitors has transformed clinical oncology, particularly for the treatment of hormone receptor-positive (HR+) breast cancer, by inducing G1 cell cycle arrest and cellular senescence [7, 8, 10]. Beyond its primary role in cell cycle control, emerging research also highlights CDK4’s involvement in modulating anti-tumor immunity and cellular metabolism, making it a complex and multifaceted target for therapeutic intervention [11, 13].

Other names

Cyclin-dependent kinase 4Cell division protein kinase 4CDK4 pathwayCMM3PSK-J3

Selective inhibitors of CDK4 and CDK6 competitively bind to the ATP-binding pocket of the kinases, preventing the formation of active CDK4/6-cyclin D complexes. This inhibition blocks the phosphorylation of the retinoblastoma (Rb) protein, keeping it in a hypophosphorylated state that sequesters E2F transcription factors and prevents the transcription of genes necessary for S-phase entry, effectively causing G1 phase cell cycle arrest [1, 5, 6, 12].