Zhang Lixiao, Liu Wei, Zheng Zhen, Zhang Qiuyue, He Yanyi, Gu Jinying, Wang Danni, Shu Huangliang, Yu Jia, Liu Jianfeng, Yin Xingyu, Zhang Lianshan, Zhang Jian, You Qidong, Wang Lei
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Angew Chem Int Ed Engl. 2025 Jan 10;64(2):e202413618. doi: 10.1002/anie.202413618. Epub 2024 Dec 2.
Cell division cycle 37 (CDC37) is a member of the molecular chaperone family and acts as a cochaperone of heat shock protein 90 (HSP90), which is overexpressed in many cancer types as a regulator of protein kinase maturation. In this process, CDC37 selectively recognizes and stabilizes protein kinases by forming a HSP90-CDC37-kinase chaperone complex. The protein-protein interactions (PPIs) of HSP90-CDC37 and CDC37-kinase complexes contribute to malignant tumors, as oncogenic kinases in malignant cells depend upon CDC37 expression. Thus, inhibiting CDC37 to disrupt HSP90-CDC37-kinase chaperone complex reveals as a promising way to achieve selective inhibition of oncogenic kinase maturation. Herein, we report a small-molecule CDC37 inhibitor called DDO-6079 that simultaneously inhibits HSP90-CDC37 and CDC37-CDK4/6 chaperone complex by binding to an allosteric site on CDC37. DDO-6079 selectively inhibited the maturation of multiple oncogenic kinases to escape heat shock response (HSR). Furthermore, DDO-6079 decreased the thermostability of CDK6, reversed the resistance of CDK6 to palbociclib (a successful CDK4/6 inhibitor) in colorectal cancer cells and exhibited efficacy in vivo. Together, the results revealed that DDO-6079 is a first-in-class small molecule CDC37 inhibitor that disrupts the HSP90-CDC37-kinase chaperone complex and provides a new way to block kinase maturation.
细胞分裂周期37（CDC37）是分子伴侣家族的成员，作为热休克蛋白90（HSP90）的共伴侣发挥作用，HSP90在许多癌症类型中作为蛋白激酶成熟的调节剂而过表达。在这个过程中，CDC37通过形成HSP90 - CDC37 - 激酶伴侣复合物选择性地识别并稳定蛋白激酶。HSP90 - CDC37和CDC37 - 激酶复合物的蛋白质 - 蛋白质相互作用（PPI）促进恶性肿瘤的发生，因为恶性细胞中的致癌激酶依赖于CDC37的表达。因此，抑制CDC37以破坏HSP90 - CDC37 - 激酶伴侣复合物是实现选择性抑制致癌激酶成熟的一种有前景的方法。在此，我们报道了一种名为DDO - 6079的小分子CDC37抑制剂，它通过与CDC37上的变构位点结合同时抑制HSP90 - CDC37和CDC37 - CDK4/6伴侣复合物。DDO - 6079选择性地抑制多种致癌激酶的成熟以逃避热休克反应（HSR）。此外，DDO - 6079降低了CDK6的热稳定性，逆转了结直肠癌细胞中CDK6对帕博西尼（一种成功的CDK4/6抑制剂）的耐药性，并在体内显示出疗效。总之，结果表明DDO - 6079是一种一流的小分子CDC37抑制剂，它破坏了HSP90 - CDC37 - 激酶伴侣复合物，并提供了一种阻断激酶成熟的新方法。
