1. Academic Validation
  2. Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation

Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation

  • J Med Chem. 2021 Oct 28;64(20):15503-15514. doi: 10.1021/acs.jmedchem.1c01539.
Lin-Sheng Zhuo 1 Ming-Shu Wang 1 Feng-Xu Wu 2 Hong-Chuang Xu 1 Yi Gong 1 Zhi-Cheng Yu 1 Yan-Guang Tian 1 Chao Pang 1 Ge-Fei Hao 1 Wei Huang 1 Guang-Fu Yang 1
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
  • 2 Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Hubei 442000, P. R. China.
Abstract

Tropomyosin receptor kinase (Trk) inhibition is an effective therapeutic approach for treatment of a variety of cancers. Despite the use of first-generation Trk Inhibitor (TRKI) larotrectinib (1) resulting in significant therapeutic response in patients, acquired resistance develops invariably. The emergence of secondary mutations occurring at the solvent-front, xDFG, and gatekeeper regions of Trk represents a common mechanism for acquired resistance. However, xDFG mutations remain insensitive to second-generation macrocyclic TRKIs selitrectinib (3) and repotrectinib (4) designed to overcome the resistance mediated by solvent-front and gatekeeper mutations. Here, we report the structure-based drug design and discovery of a next-generation TRKI. The structure-activity relationship studies culminated in the identification of a promising drug candidate 8 that showed excellent in vitro potency on a panel of Trk mutants, especially TrkAG667C in the xDFG motif, and improved in vivo efficacy than 1 and 3 in Trk wild-type and mutant fusion-driven tumor xenograft models, respectively.

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