Fulcrum Occupancy-Leverage Perturbation Strategy Enables Rapid Discovery of Potent CDK2-Cyclin A2 Interaction Inhibitors
文献类型：期刊论文
| 作者 | Sun, Ge4,5; Chi, Shuaishuai4,6; Li, Jiacheng4,5; Xu, Pan4,5; Lin, Tingting5; Chen, Chao4,7; Liu, Liping4,5; Yang, Yulin4,5; Yan, Ruyu2,4,5; Han, Hongbo4,5 |
| 刊名 | ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
 |
| 出版日期 | 2025-08-19 |
| 页码 | 14 |
| 关键词 | CDK2-Cyclin A2 Inhibitor design strategy Melanoma Protein-protein interaction |
| DOI | 10.1002/anie.202513542 |
| 英文摘要 | Traditional strategies for developing small-molecule inhibitors of protein-protein interactions (PPIs) are time-consuming and often yield low success rates due to the flat and dynamic interfaces of PPIs. To enable the rapid design of highly potent PPI inhibitors, we proposed a novel strategy named "Fulcrum Occupancy-Leverage Perturbation (FOLP)". In this strategy, high-affinity fragments serve as the "Fulcrum" by binding to the orthosteric pocket, while suitable moieties extend into allosteric sites near the PPI interface as "Leverage" to modulate the protein-protein interaction. As a proof of concept, the potent CDK2-Cyclin A2 PPI inhibitor LC-K2CAin-3, which fits the "FOLP" paradigm, was discovered with an IC50 of 32.1 nM for inhibiting the interaction. Molecular dynamics simulations and cryptic pocket identification were employed, revealing the activation loop (A-loop) of CDK2 was flexible and targetable. X-ray crystallography and hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis showed that LC-K2CAin-3 indeed bound to and stabilized the A-loop. LC-K2CAin-3 effectively inhibited the CDK2-Cyclin A2 interaction in CDK2 highly expressed melanoma cells, leading to cell cycle arrest and apoptosis and inhibition of CDK2 mediated signaling. In conclusion, the "FOLP" strategy offers a novel approach for PPI inhibitor discovery and could accelerate the development of PPI inhibitors. |
| WOS关键词 | PROTEIN-PROTEIN INTERACTIONS ; STRUCTURAL BASIS ; SMALL MOLECULES ; CELL-CYCLE ; CANCER ; IDENTIFICATION ; ACTIVATION ; INITIATION ; TARGETS |
| 资助项目 | Program of Shanghai Academic Research Leader |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001552334600001 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321252]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Chen, Shijie; Chen, Yi; Zhou, Bing; Luo, Cheng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 3.East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Zhejiang Univ, Sch Med, Dept Basic Med Sci, Hangzhou 310058, Zhejiang, Peoples R China 7.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 8.Guizhou Med Univ, Sch Pharm, State Key Lab Funct & Applicat Med Plants, Guiyang 550004, Peoples R China 9.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Shanghai 528400, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Ge,Chi, Shuaishuai,Li, Jiacheng,et al. Fulcrum Occupancy-Leverage Perturbation Strategy Enables Rapid Discovery of Potent CDK2-Cyclin A2 Interaction Inhibitors[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2025:14. |
| APA | Sun, Ge.,Chi, Shuaishuai.,Li, Jiacheng.,Xu, Pan.,Lin, Tingting.,...&Luo, Cheng.(2025).Fulcrum Occupancy-Leverage Perturbation Strategy Enables Rapid Discovery of Potent CDK2-Cyclin A2 Interaction Inhibitors.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,14. |
| MLA | Sun, Ge,et al."Fulcrum Occupancy-Leverage Perturbation Strategy Enables Rapid Discovery of Potent CDK2-Cyclin A2 Interaction Inhibitors".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2025):14. |
入库方式： OAI收割
来源：上海药物研究所
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