Cyclin-dependent kinase 2
Cyclin-dependent kinase 2
Overview
Cyclin-dependent kinase 2 (CDK2) is a serine/threonine protein kinase that functions as a core regulator of cell-cycle progression. In normal biology, CDK2 acts in concert with cyclins to control transitions through the G1/S boundary and S phase, thereby coordinating DNA replication and cell proliferation. Because of this central role in cell-cycle control, CDK2 is widely studied in oncology and drug discovery as a target for suppressing uncontrolled tumor growth.
In recent biomedical research, CDK2 has been especially relevant in cancers that evade Cdk4/6 inhibitor therapy or show CCNE1 amplification, both of which can indicate dependence on CDK2-driven cell-cycle signaling. It is also frequently evaluated alongside related kinases such as CDK6, cyclin-dependent kinase 1, and Aurora kinase A, as well as pathway-associated proteins including B-cell lymphoma 2, caspase-3, and Mki67, to understand how cell-cycle arrest, apoptosis, and proliferation are altered by candidate therapies.
Focus of Latest Publications
Recent publications have continued to position cyclin-dependent kinase 2 (CDK2) as a therapeutically relevant target in cancer, with studies spanning medicinal chemistry, structural biology, computational screening, and functional validation. Several reports focused on designing small-molecule CDK2 inhibitors or dual-target agents. In hepatocellular carcinoma and colorectal cancer models, candidate compounds were evaluated for antiproliferative activity, kinase inhibition, and effects on cell-cycle progression. One series of 4,5,6,7-tetrahydrobenzo[b]thiophene carboxamides showed CDK2 inhibitory activity, with one analogue reported to inhibit CDK2 more strongly than roscovitine and to induce G0/G1 arrest in breast cancer cells. Another scaffold, 1,2,4-triazolo[1,5-a]pyrimidines, was developed as dual EGFR/CDK2 inhibitors and produced G2/M arrest and apoptosis in HCT-116 cells, with one lead showing a CDK2 IC50 of 0.03 μM.
Structural and degradation-based strategies have also been highlighted. A recent study identified cereblon-based molecular glue degraders, B10 and B12, that selectively degrade CDK2 through a noncanonical recruitment mode centered on CDK2 Glu57. These degraders inhibited retinoblastoma protein phosphorylation, induced G1/S-phase arrest, and suppressed CDK2-dependent proliferation; B12 additionally showed oral bioavailability and intratumoral CDK2 degradation in vivo. In parallel, computational studies screened natural products and phytochemicals against CDK2 as part of multi-target anticancer approaches. Examples include Pinellia ternata constituents predicted to interact with CDK2 in lung cancer-related target networks, and garlic-derived organosulfur compounds, particularly Z-ajoene, predicted to bind CDK2 among other breast cancer biomarkers.
Functional studies further support CDK2 as a driver of tumor progression in specific contexts. In glioblastoma, Aucan was reported to suppress proliferation, migration, invasion, and tumor growth by downregulating CDK2 and inhibiting PI3K/AKT signaling; CDK2 knockdown phenocopied the compound’s effects. In lung adenocarcinoma, the circRNA-encoded protein RIPK1-98 was found to modulate CDK2-dependent cell-cycle regulation and promote tumor proliferation. These findings reinforce CDK2’s role in cell-cycle control and tumor growth across multiple malignancies.
Across the recent literature, CDK2 has been linked most consistently to cell-cycle arrest, apoptosis, and suppression of oncogenic signaling pathways such as PI3K/AKT and PTEN/AKT/p53. In hepatocellular carcinoma, CNOT9 knockdown reduced expression of CDK2 alongside p53, p21, and CCNE1, while activating PTEN and inhibiting AKT signaling. Together, these studies underscore ongoing interest in CDK2 as both a direct drug target and a downstream effector in cancer biology, with emerging approaches including selective inhibition, targeted degradation, and multi-target compound design.