Cyclin-dependent kinase 2 (CDK2) (CDK2)

Cyclin-dependent kinase 2 (CDK2) is a member of the serine/threonine protein kinase family and a key component of the cell-cycle machinery [1, 10]. It primarily regulates the transition from the G1 to the S phase and the progression through the S phase by forming complexes with regulatory subunits, specifically Cyclin E and Cyclin A [2, 10]. These complexes phosphorylate critical substrates like the retinoblastoma (Rb) protein, which releases E2F transcription factors to initiate DNA replication [4, 17]. In many cancers, such as breast and ovarian cancer, CDK2 is overactive due to the amplification or overexpression of Cyclin E1 (CCNE1), leading to uncontrolled cell division [5, 9, 13]. This hyperactivation is also a major mechanism of resistance to CDK4/6 inhibitors in hormone receptor-positive breast cancer [11, 14]. Therapeutic strategies focus on small-molecule inhibitors that compete with ATP for the binding site of CDK2, effectively halting the cell cycle and inducing apoptosis [2, 4]. Recent drug development has prioritized highly selective CDK2 inhibitors to avoid the toxicity associated with inhibiting the closely related and essential CDK1 [15, 21]. These selective agents, such as PF-07104091 and BLU-222, are currently being evaluated in clinical trials both as monotherapy and in combination with other targeted therapies [3, 7, 11].

Other names

Cell division protein kinase 2p33 protein kinaseCDK2

Inhibition of the kinase activity of CDK2 by competing with ATP for the binding site, preventing phosphorylation of substrates like the retinoblastoma (Rb) protein and thereby arresting the cell cycle at the G1/S phase transition [2, 4, 10].