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Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src

Lingzhi Qu1, Hang Lin1, Shuyan Dai1

  • 1Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Computational and Structural Biotechnology Journal
|December 11, 2023
PubMed

Insights

TPX-0022, a novel inhibitor targeting c-Met, c-Src, and CSF1R kinases, shows potent activity against various cancer mutations. Structural analysis reveals its binding mechanism, offering insights into overcoming drug resistance in advanced solid tumors.

Area of Science:

  • Oncology
  • Structural Biology
  • Pharmacology

Background:

  • The c-Met receptor tyrosine kinase is a significant target in cancer therapy due to its role in tumor growth and metastasis.
  • TPX-0022 is an investigational macrocyclic inhibitor targeting c-Met, c-Src, and CSF1R, currently in clinical trials for advanced solid tumors with MET alterations.

Purpose of the Study:

  • To elucidate the binding mechanism of TPX-0022 to c-Met and c-Src through co-crystal structure determination.
  • To understand TPX-0022's activity against various c-Met resistance mutations.

Main Methods:

  • Co-crystal structures of c-Met/TPX-0022 and c-Src/TPX-0022 complexes were determined.
  • Biochemical assays were performed to evaluate TPX-0022 activity against wild-type and mutant forms of c-Met.

Main Results:

  • TPX-0022 binds to the ATP pocket of c-Met and c-Src, stabilized by hydrophobic and hydrogen bond interactions.
  • TPX-0022 demonstrated potent activity against the L1195F mutant and moderate activity against G1163R, F1200I, and Y1230H mutants.
  • Weak activity was observed against c-Met D1228N and Y1230C mutants, indicating differential efficacy against specific resistance mutations.

Conclusions:

  • The study reveals the structural basis for TPX-0022's potency and selectivity against c-Met and c-Src.
  • TPX-0022 demonstrates the potential to overcome acquired resistance mutations in c-Met.
  • Findings provide valuable insights for developing next-generation selective c-Met macrocyclic inhibitors.
Keywords:
C-MetC-SrcCrystal structureResistance-relevant mutationsTPX-0022

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