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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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

Long-Can Mei1, Lin-Sheng Zhuo1, Hong-Chuang Xu1

  • 1Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China.

European Journal of Medicinal Chemistry
|April 29, 2022
PubMed

Insights

A new drug design strategy overcomes multiple mutations causing cancer drug resistance. The developed inhibitor TIY-7 effectively targets tropomyosin receptor kinase (TRK) mutants, showing promise for improved cancer therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Drug Discovery

Background:

  • Mutation-induced drug resistance is a significant challenge in cancer chemotherapy.
  • Multiple resistance mutations in targeted therapies, particularly for tropomyosin receptor kinases (TRKs), limit treatment efficacy.
  • TRKs are crucial targets in various cancers, but resistance development necessitates novel therapeutic strategies.

Purpose of the Study:

  • To develop a novel drug design strategy to overcome multiple resistance mutations in cancer treatment.
  • To evaluate the efficacy of a new inhibitor designed using a conformational adjustment strategy against TRK mutants.
  • To compare the performance of the novel inhibitor with existing clinical drugs.

Main Methods:

  • Proposed a conformational adjustment strategy for drug design.
  • Synthesized and tested a representative inhibitor (TIY-7) against multiple TRK mutants.
  • Assessed tumor growth inhibitory activity in vivo and compared it with selitrectinib.

Main Results:

  • TIY-7 demonstrated potent inhibitory activity against five TRK mutants, with an IC50 of 1.1 nM against TRKA-G595R.
  • The inhibitor exhibited superior tumor growth inhibition compared to the clinically used drug selitrectinib.
  • The conformational adjustment strategy proved effective in overcoming multiple resistance mutations.

Conclusions:

  • The conformational adjustment strategy is a viable approach to design inhibitors that overcome multiple drug resistance mutations.
  • TIY-7 represents a promising therapeutic candidate for cancers driven by TRK alterations, even in the presence of resistance mutations.
  • This strategy offers a potential solution to enhance the long-term effectiveness of targeted cancer therapies.
Keywords:
Cancer treatmentDrug modificationDrug resistanceMultiple resistance mutationsTRK inhibitor

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