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.

Key Publications

• NEWJul CNOT9 affects hepatocellular carcinoma proliferation and cell cycle through the PTEN/AKT/p53 signaling pathway. (Human cell, 2026, PMID 42384246): "CNOT9 knockdown activates PTEN to inhibit the AKT pathway and suppresses the expression of cell cycle-related proteins p53, p21, CCNE1 and CDK2."
• NEWJun Selective CDK2 Degradation via Noncanonical Recruitment. (Journal of medicinal chemistry, 2026, PMID 42334090): "Cyclin-dependent kinase 2 (CDK2) represents a critical therapeutic target in tumors resistant to CDK4/6 inhibitors or with CCNE1 amplification."
• NEWJun Phenothiazine dye-loaded chitosan cryogels as multifunctional antibacterial wound dressings. (Scientific reports, 2026, PMID 42324341): "Further, the molecular docking analysis showed that PTZ-chalcone has a high binding affinity for proteins (CDK6 and CDK2), suggesting potential applications in combating bacterial infections and cancer."
• May Design, synthesis, anticancer activity, and mechanistic investigation of 4,5,6,7-tetrahydrobenzo[b]thiophene carboxamides as CDK-2 inhibitors: in vitro and in silico DFT and molecular docking study. (Journal of enzyme inhibition and medicinal chemistry, 2026, PMID 42210722): "as CDK-2 inhibitors."
• Jun Lead Discovery via Scaffold Refinement: Structure-Guided Optimization of 1,2,4-Triazolo[1,5-a]Pyrimidines as Potent Dual EGFR/CDK-2 Inhibitors Targeting Colorectal Carcinoma. (Drug development research, 2026, PMID 42200498): "A unique series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed and synthesized as potential dual inhibitors of EGFR and CDK-2 to circumvent drug resistance in colorectal cancer patients through multi-targeted therapy."
• May In-silico prediction of multi‑target mechanisms of Pinellia ternata phytochemicals in lung cancer: Evidence from a graph‑attention‑guided virtual screening and multi‑scale simulations. (PloS one, 2026, PMID 42149884): "the potential targets of Pinellia ternata highly overlap with lung cancer pathological genes, with FGFR4, CDK2, JAK2, KDR, PAK4, PTK2 and PDGFRA being the core."
• May In silico evaluation of garlic-derived organosulfur compounds as multi-target inhibitors of breast cancer biomarkers. (PloS one, 2026, PMID 42090396): "Z-ajoene showed strong binding to Bcl-2, Topoisomerase II, and CDK-2, while S-allyl-L-cysteine targets five biomarkers."
• Jun Design and synthesis of novel 1,2,4-triazolobenzene sulfonamide derivatives as selective CDK1 inhibitors with potent in vivo anticancer efficacy. (European journal of medicinal chemistry, 2026, PMID 41903286): "Among them, 11l emerged as a highly promising lead compound, exhibiting nanomolar inhibitory activity against CDK1 (IC50=5.5 nM) with high selectivity over CDK2, Aurora A, and CDK4, showing selectivity indices of 4.7-, 14.1-, and 73.2-fold, respectively."
• Mar Aucan targets CDK2 to suppress glioblastoma progression by inhibiting PI3K/AKT pathway-mediated proliferation and inducing apoptosis. (Biochemical pharmacology, 2026, PMID 41846012): "Integrative bioinformatics identified CDK2 as a key target, with single-cell data showing CDK2 overexpression in malignant astrocytic populations."
• May CircRNA-encoded RIPK1-98 protein drives lung adenocarcinoma progression. (Developmental cell, 2026, PMID 41825439): "RIPK1-98 modulates cyclin-dependent kinase 2 (CDK2)-dependent cell-cycle regulation, thereby facilitating tumor proliferation in cellular and animal models."