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
  • 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.
PMID: 34668694 DOI: 10.1021/acs.jmedchem.1c01539
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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