Five new series of pyrazolo[1,5-a]pyrimidine derivatives were synthesized as potential anti-cancer agents targeting the CDK2 enzyme. Their cytotoxic activity was evaluated against colon cancer (HCT-116) and breast cancer (MDA-MB-231) cell lines. Among the tested compounds, 7-(4-bromophenyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidine-3‑carbonitrile (13 g), 7-(2,4-dichlorophenyl)-2-(methylthio)pyrazolo[1,5-a]pyrimidine-3‑carbonitrile (13j), 7-[1-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-yl)-2-(methylthio)pyrazolo[1,5-a] pyrimidine-3‑carbonitrile (21c), and 7-(6-bromo-2-oxo-2H-chromen-3-yl)-2-(methylthio)pyrazolo[1,5-a] pyrimidine-3‑carbonitrile (26b) exhibited strong growth inhibition in HCT-116 cells, comparable to the reference drug roscovitine. Compounds 13 g and 21c were identified as the most potent candidates against HCT-116 cells, with IC₅₀ values of 0.45 μM and 0.09 μM, respectively, compared to roscovitine (IC₅₀ = 0.07 μM). Moreover, compounds 13 g, 13j, 21c, and 26b also displayed low toxicity toward normal WI-38 fibroblast cells, indicating superior selectivity. CDK2 inhibition assay for the most potent compounds 13 g, 13j, and 21c, demonstrated promising IC₅₀ values ranging from 18 to 150 nM, compared to roscovitine (IC₅₀ = 140 nM). Further biological evaluation revealed that compound 21c (IC₅₀ = 18 nM) triggered G1-phase cell cycle arrest and promoted more apoptosis than necrosis in HCT-116 cells (total apoptosis: 32.96 % compared to 0.63 % in the control). RT-PCR analysis indicated that apoptosis was mediated through both intrinsic and extrinsic pathways, accompanied by downregulation of the anti-apoptotic gene BCL-2 (0.7-fold change). Molecular docking studies supported these results, showing favorable interactions of compound 21c within the CDK2 active site. Overall, compound 21c emerges as a promising lead candidate for the development of selective CDK2 inhibitors exhibiting potent anti-cancer activity and low toxicity toward normal cells.

2026-02-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Synthesis and discovery of guaianolide ‐ eudesmanolide heterodimers as CDK2 inhibitors for the treatment of hepatocellular carcinoma

Article

作者: Wang, Yong-Cui ; Huang, Feng-Dan ; Hu, Min-Min ; Li, Feng-Jiao ; Ma, Yun-Bao ; Li, Tian-Ze ; Chen, Ji-Jun ; Yang, Yao

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, creating an urgent need for novel therapeutic agents with unique mechanisms. Inspired by the antiHCC properties of natural sesquiterpenoid dimers and to overcome their limited structural diversity and availability, 26 new guaianolide-eudesmanolide heterodimers were synthesized via Diels-Alder reactions. AntiHCC assay suggested 19 analogues showed better inhibitory activity than sorafenib on HepG2, SK-Hep-1, and Huh7 cells. Surprisingly, chlorinated dimer 10 showed exceptional activity with IC₅₀ values 3.9-6.1 fold superior to sorafenib, inhibited migration and invasion, and induced apoptosis. CDK2 was identified as the target of compound 10 as confirmed by CETSA, DARTS, and functional knockdown assays. Molecular docking and molecular dynamics simulations predicted that compound 10 acted as a novel non-ATP-competitive inhibitor of CDK2. Compound 10 inhibited CDK2/Cyclin A2 with an IC₅₀ value of 236.7 nM, disrupted their interaction, promoted CDK2 degradation via the lysosomal pathway, and ultimately induced G0/G1 phase cell cycle arrest and cellular senescence. In vivo, dimer 10 at 30 and 60 mg/kg inhibited tumor weight up to 64 % and 69 % without detectable toxicity, and IHC analysis confirmed in vivo target engagement. This study identified compound 10 as a potential antiHCC agent targeting CDK2, and warrants further investigation.

2025-10-01·BIOCHEMICAL PHARMACOLOGY

Licoisoflavone A inhibits colorectal cancer cell proliferation through targeting CDK2-Cyclin E1 axis-mediated cell cycle transition

Article

作者: Huang, Chuyue ; Wang, Lu ; Cui, Jingwei ; Chen, Hao ; Gong, Puyang ; Wang, Pei ; Zhou, Bingwen ; Chen, Yuru ; Fan, Zhimin

As the second most malignant neoplasm in the world, colorectal cancer (CRC) still needs the novel treatment strategy urgently. Cyclin-dependent kinase 2 (CDK2) has been identified as a potential therapeutic target in CRC research, but the development of CDK2 inhibitors still faces significant challenges. This study was to investigate the efficacy and underlying mechanisms of licoisoflavone A (LA) in targeting CDK2. HCT116 and SW480 human CRC cells were used to evaluate the in vitro anti-CRC activity and CDK2 regulation effect of LA by flow cytometry and Western blot analysis. Molecular docking and CDK2 knockdown cell models were used to investigate the direction interaction between LA and CDK2. Patient-derived CRC organoids and tumor-bearing mice were used to verify the anti-CRC activity and mechanism of LA. As a result, LA significantly inhibited cell proliferation and induced G1/S phase arrest in HCT116 and SW480 cells. LA had direct interaction with CDK2, and not only inhibited the formation of the CDK2/cyclin E1 complex, but also suppressed its kinase activity through the upregulation of p27, thereby inhibiting Rb phosphorylation and arresting the cell cycle in the G1 phase. Moreover, LA exerted anti-CRC effect in CRC organoids and the subcutaneous xenograft tumor mode without evident toxic effects. LA inhibits CRC cell proliferation through targeting the CDK2-Cyclin E1 axis-mediated cell cycle transition. Our research provides compelling evidence that LA may serve as a potential agent for the treatment of CRC, and also provides a rationale to design novel CDK2 inhibitors.

项与 CDK2 inhibitors(Gwangju Institute of Science & Technology) 相关的新闻（医药）

2023-11-16

·SYNAPSE

What are CDK2 inhibitors and how do you quickly get the latest development progress?

CDK2, or cyclin-dependent kinase 2, is a crucial protein involved in cell cycle regulation in the human body. It plays a pivotal role in controlling the progression of cells from the G1 phase to the S phase, allowing DNA replication and cell division to occur. CDK2 forms complexes with cyclins, which activate its kinase activity, leading to the phosphorylation of various target proteins involved in cell cycle progression. The CDK2/cyclin E complex plays a crucial role in the phosphorylation of retinoblastoma (Rb) protein and the transition from G1/S phase. The CDK2/cyclin A complex is significantly involved in DNA synthesis during the S phase and the activation of CDK1/cyclin B during the transition from G2/M phase. PF-07104091(19) is an orally available CDK2 inhibitor with a potential antitumor activity. In human ovarian cancer cell models(OVCAR3, OV5392), compound 19(25, 75 and 175mg/kg, twice daily, po) can induce tumor reduction in a dose-dependent manner. Furthermore, the combined administration of 19 and the frontline drug Palbociclib demonstrated a synergistic effect in the model of breast cancer cells. In 2020, Pfizer initiated a Phase I/II clinical trial of compound 19 to assess its safety and tolerance and to test the maximum tolerated dose of compound 19 as a single therapy in patients with small cell lung cancer, non-small cell lung cancer, ovarian cancer or breast cancer(NCT04553133). Dysregulation of CDK2 activity has been implicated in numerous diseases, including cancer, making it an attractive target for therapeutic interventions aimed at controlling cell proliferation and promoting healthy cell cycle prThe target CDK2 in the pharmaceutical industry has attracted the attention of several companies, including Pfizer Inc., Cyclacel Pharmaceuticals, Inc., Otsuka Holdings Co., Ltd., and Tiziana Life Sciences Ltd. These companies are actively involved in the research and development of drugs targeting CDK2. Indications such as non-small cell lung cancer, ovarian cancer, and triple negative breast cancer have seen the approval of drugs targeting CDK2. The most rapidly progressing drug types under the target CDK2 are small molecule drugs, indicating intense competition in this area. The European Union and the United States are leading in terms of development, with China also making progress. Overall, the competitive landscape for target CDK2 is dynamic, and future development in this area holds significant potential.ogression. How do they work?CDK2 inhibitors are a type of drugs that specifically target and inhibit the activity of cyclin-dependent kinase 2 (CDK2). CDK2 is a protein kinase that plays a crucial role in regulating the cell cycle, specifically the transition from the G1 phase to the S phase. By inhibiting CDK2, these inhibitors can disrupt the cell cycle progression and prevent the proliferation of cancer cells. From a biomedical perspective, CDK2 inhibitors are of great interest in the field of cancer research and treatment. Cancer cells often exhibit uncontrolled cell division and proliferation, and CDK2 is frequently overactive in these cells. By blocking CDK2 activity, CDK2 inhibitors can potentially halt the growth of cancer cells and serve as a targeted therapy for various types of cancer. It's important to note that CDK2 inhibitors are still under investigation and development, and their clinical use is currently limited to clinical trials. These inhibitors hold promise as potential anticancer agents, but further research is needed to determine their efficacy, safety, and optimal usage in cancer treatment. List of CDK2 InhibitorsThe currently marketed CDK2 inhibitors include: AT-7519Milciclib maleatePF-06873600PF-07104091SeliciclibARTS-021BLU-222FadraciclibINX-315DinaciclibFor more information, please click on the image below. What are CDK2 inhibitors used for?CDK2 inhibitors are under investigation forIndications such as non-small cell lung cancer, ovarian cancer, and triple negative breast cancer.For more information, please click on the image below to log in and search. How to obtain the latest development progress of CDK2 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of CDK2 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与 CDK2 inhibitors(Gwangju Institute of Science & Technology) 相关的药物交易

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