2. Academic Validation
  3. Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors

Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors

  • Eur J Med Chem. 2025 Mar 5:285:117231. doi: 10.1016/j.ejmech.2024.117231.
Shaoshan Xu 1,  Xiaosheng Jiang 2,  Mengdi Xu 1,  Chengjian Ai 1,  Guanyi Zhao 1,  Tao Jiang 1,  Yang Liu 1,  Zhen Tian 1,  Meihui Zhang 3,  Jinhua Dong 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 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.
  • 3 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: zhangmeihui@syphu.edu.cn.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: jhdong@syphu.edu.cn.
PMID: 39778327 DOI: 10.1016/j.ejmech.2024.117231
Abstract

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 (t1/2 > 480 min) and moderate liver microsomal stability (t1/2 = 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.

Keywords

1H-indole-3-carbonitrile; Anticancer; NTRK gene fusion; TRK inhibitors.

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