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  3. Conformational adjustment overcomes multiple drug-resistance mutants of tropomyosin receptor kinase

Conformational adjustment overcomes multiple drug-resistance mutants of tropomyosin receptor kinase

  • Eur J Med Chem. 2022 Jul 5;237:114406. doi: 10.1016/j.ejmech.2022.114406.
Long-Can Mei 1,  Lin-Sheng Zhuo 1,  Hong-Chuang Xu 1,  Wei Huang 2,  Ge-Fei Hao 3,  Guang-Fu Yang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
  • 2 Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China. Electronic address: weihuangwuhan@126.com.
  • 3 Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China. Electronic address: gefei_hao@foxmail.com.
  • 4 Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China. Electronic address: gfyang@mail.ccnu.edu.cn.
PMID: 35486994 DOI: 10.1016/j.ejmech.2022.114406
Abstract

Mutation-induced resistance to targeted drug treatment poses a serious threat to successful chemotherapy. Multiple mutations underlying drug resistance remain a largely unsolved scientific issue. Tropomyosin receptor kinases (TRKs) are promising therapeutic targets for several malignant human cancers, but they have become less effective due to multiple resistance mutations. Thus, TRKs are representative cases to explore the problem of multiple resistance mutations. Here, we proposed a conformational adjustment strategy of drug design to overcome multiple resistance mutations in Cancer treatments. A representative inhibitor, TIY-7, exhibited remarkable inhibitory activity against five Trk mutants, showing an IC50 value of 1.1 nM against the most severe mutant TRKA-G595R. Moreover, it displayed superior tumor growth inhibitory activity compared with the clinically used drug selitrectinib. These results validated our strategy to design a new inhibitor structure to overcome multiple resistance mutations.

Keywords

Cancer treatment; Drug modification; Drug resistance; Multiple resistance mutations; TRK inhibitor.

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