Xu Mingjin, Wu Kaifu, He Rui, He Jiahuan, Yang Gangpeng, Ma Haowen, Peng Lijie, Zhang Shuyao, Tan Li, Zhang Zhang, Cai Qian
College of Chemistry and Materials Science, Zhejiang Normal University, No. 688 Yingbin Road, Jinhua, Zhejiang Province, 321004, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
State Key Laboratory of Bioactive Molecules and Druggability Assessment, School of Pharmacy, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
Eur J Med Chem. 2025 Mar 15;286:117294. doi: 10.1016/j.ejmech.2025.117294. Epub 2025 Jan 23.
RET is a well-recognized drug target for cancer treatment. Despite the promising efficacy of selective second-generation RET inhibitors Selpercatinib and Pralsetinib, the clinical benefits have been compromised due to the quickly developed resistance to these drugs. RET G810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against Selpercatinib and Pralsetinib. Therefore, there is an urgent need for the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations. In this study, a series of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives have been identified as selective next-generation RET inhibitors. The representative compound, CQ1373 exhibits potent cellular potency with IC values of 13.0, 25.7 and 28.4 nM against BaF3 cells expressing CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R, respectively. A comprehensive selectivity profile across 89 kinases reveals that CQ1373 demonstrates good selectivity toward wild-type RET and solvent front mutants G810C/R with IC values of 4.2, 7.1 and 32.4 nM, respectively. Furthermore, western blot analysis reveals that CQ1373 effectively inhibits RET phosphorylation and downstream signaling through SHC. It also induces apoptosis and cell cycle arrest in a dose-dependent manner in BaF3 cells harboring CCDC6-RET, CCDC6-RET-G810C and CCDC6-RET-G810R fusions. More significantly, CQ1373 exhibits promising in vivo anti-tumor efficacy in a CCDC6-RET-G810R mice xenograft model, highlighting its potentials for RET-driven cancers treatment.
RET是一种公认的癌症治疗药物靶点。尽管选择性第二代RET抑制剂塞尔帕替尼（Selpercatinib）和普拉替尼（Pralsetinib）具有良好的疗效，但由于对这些药物的耐药性迅速产生，其临床益处受到了影响。在溶剂前沿位点的RET G810突变已被确定为导致对塞尔帕替尼和普拉替尼耐药的主要靶点上的突变。因此，迫切需要开发新一代RET抑制剂以克服获得性溶剂前沿耐药突变。在本研究中，一系列（E）-1-（4-（2-（1H-吡唑-5-基）乙烯基）苯基）衍生物已被鉴定为选择性新一代RET抑制剂。代表性化合物CQ1373对表达CCDC6-RET、CCDC6-RET-G810C和CCDC6-RET-G810R的BaF3细胞表现出强大的细胞活性，IC值分别为13.0、25.7和28.4 nM。对89种激酶的全面选择性分析表明，CQ1373对野生型RET和溶剂前沿突变体G810C/R具有良好的选择性，IC值分别为4.2、7.1和32.4 nM。此外，蛋白质印迹分析表明，CQ1373通过SHC有效抑制RET磷酸化和下游信号传导。它还以剂量依赖的方式诱导携带CCDC6-RET、CCDC6-RET-G810C和CCDC6-RET-G810R融合体的BaF3细胞凋亡和细胞周期停滞。更重要的是，CQ1373在CCDC6-RET-G810R小鼠异种移植模型中表现出有前景的体内抗肿瘤疗效，突出了其在RET驱动的癌症治疗中的潜力。
