Cell cycle kinases

Cell cycle kinases are a diverse group of serine/threonine protein kinases that orchestrate the orderly progression of the cell division cycle [11, 15, 19, 20]. This family includes the cyclin-dependent kinases (CDKs), Aurora kinases, Polo-like kinases (PLKs), and checkpoint kinases (Chks), which collectively regulate transitions between phases (G1, S, G2, and M) and ensure genomic integrity through various checkpoints [4, 13, 19, 21]. Dysregulation of these kinases, often through overexpression of their cyclin activators or loss of endogenous inhibitors like p16, is a hallmark of many cancers, leading to uncontrolled cellular proliferation [11, 15, 19, 24]. Consequently, they have become major therapeutic targets in oncology, with several inhibitors approved for clinical use [1, 3, 4, 7, 9, 11, 14, 19]. Drugs such as palbociclib, ribociclib, and abemaciclib specifically target CDK4 and CDK6 to treat hormone receptor-positive breast cancer by inducing G1 phase arrest [1, 6, 10, 18]. Other inhibitors targeting Aurora or PLK families aim to disrupt mitosis and induce apoptosis in various solid and hematological malignancies [4, 13]. Therapeutic challenges include managing off-target toxicities like neutropenia and overcoming resistance mechanisms such as RB1 loss or bypass signaling [16, 18, 23, 25]. Ongoing research explores the potential of these inhibitors in combination with immunotherapy or other targeted agents to enhance efficacy [7, 14, 17, 23]. Overall, cell cycle kinases represent a critical node in cancer biology and a cornerstone of modern targeted therapy [11, 14, 19, 24].

Other names

Cell cycle-dependent kinases [21]Mitotic kinases [4, 13]Cyclin-dependent kinases [1, 6, 15, 19, 20]Aurora kinases [4, 13]Polo-like kinases [4, 13]Checkpoint kinases [4, 13, 19]

Cell cycle kinases are targeted by small-molecule inhibitors that typically bind to the ATP-binding pocket of the catalytic subunit, thereby preventing the phosphorylation of downstream substrates such as the retinoblastoma (RB) protein [6, 10, 12, 15]. This inhibition leads to cell cycle arrest at specific phases (e.g., G1/S or G2/M), induction of cellular senescence, or apoptosis [1, 10, 13, 14, 18, 24]. Some newer agents also utilize allosteric inhibition or targeted protein degradation (PROTACs) to achieve greater selectivity and overcome resistance [7, 11, 14, 20].