Xu Shaoshan, Jiang Xiaosheng, Xu Mengdi, Ai Chengjian, Zhao Guanyi, Jiang Tao, Liu Yang, Tian Zhen, Zhang Meihui, Dong Jinhua
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Department of Chemistry and Biochemistry, Warren Family Research Center for Drug Discovery and Development, University of Notre Dame, Notre Dame, IN, 46556, USA.
Eur J Med Chem. 2025 Mar 5;285:117231. doi: 10.1016/j.ejmech.2024.117231. Epub 2025 Jan 3.
Tropomyosin receptor kinase (TRK) has emerged as a promising therapeutic target in cancers driven by NTRK gene fusions. Herein, we report a highly potent TRK inhibitor, C11, developed using bioisosteric replacement and computer-aided drug design (CADD) strategies. Compound C11 demonstrated significant antiproliferative effects against TRK-dependent cell lines (Km-12), and exhibited a dose-dependent inhibition of both colony formation and cell migration. Mechanistic study revealed that C11 induced cancer cell death by arresting the cell cycle, triggering apoptosis, and reducing phosphorylated TRK levels. In vitro stability assays showed that compound C11 possessed excellent plasma stability (t > 480 min) and moderate liver microsomal stability (t = 38.9 min). Pharmacokinetic evaluation further indicated an oral bioavailability of 15.2 % for compound C11. These results highlight compound C11 as a promising lead compound for the further development of TRK inhibitors.
原肌球蛋白受体激酶（TRK）已成为由NTRK基因融合驱动的癌症中有前景的治疗靶点。在此，我们报告一种使用生物电子等排体替代和计算机辅助药物设计（CADD）策略开发的高效TRK抑制剂C11。化合物C11对TRK依赖性细胞系（Km-12）表现出显著的抗增殖作用，并对集落形成和细胞迁移均呈现剂量依赖性抑制。机制研究表明，C11通过使细胞周期停滞、触发细胞凋亡以及降低磷酸化TRK水平诱导癌细胞死亡。体外稳定性试验表明，化合物C11具有优异的血浆稳定性（t>480分钟）和中等的肝微粒体稳定性（t=38.9分钟）。药代动力学评估进一步表明化合物C11的口服生物利用度为15.2%。这些结果突出了化合物C11作为TRK抑制剂进一步开发的有前景的先导化合物。
