Related Experiment Video

Updated: Jun 20, 2025

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.1K

Discovery of novel indazole derivatives as second-generation TRK inhibitors

Qiaohua Qin1, Shuyu Lu1, Zhiqiang Guo1

  • 1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.

European Journal of Medicinal Chemistry
|July 21, 2024
PubMed

Insights

New indazole TRK inhibitors combat cancer by targeting NTRK gene fusions. Compound B31 shows potent activity against resistant mutations, offering a promising therapeutic strategy for NTRK fusion-positive cancers.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • NTRK gene fusions are oncogenic drivers in various cancers.
  • First-generation TRK inhibitors (larotrectinib, entrectinib) face resistance.
  • Development of next-generation TRK inhibitors is crucial.

Purpose of the Study:

  • Design and synthesize novel indazole TRK inhibitors.
  • Evaluate antiproliferative activities against resistant cell lines.
  • Assess compound B31's efficacy and pharmacokinetic properties.

Main Methods:

  • Molecular hybridization strategy for inhibitor design.
  • Synthesis of novel indazole TRK inhibitors.
  • In vitro antiproliferative assays and in vivo pharmacokinetic studies.

Main Results:

  • Compound B31 demonstrated potent activity against Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell lines (IC50: 0.3, 4.7, 9.9 nM).
  • B31 showed superior inhibition against TRKAG667C compared to selitrectinib.
  • Compound B31 exhibited moderate kinase selectivity and excellent plasma stability (t1/2 > 480 min).

Conclusions:

  • Novel indazole TRK inhibitors were successfully designed and synthesized.
  • Compound B31 is a promising candidate for treating NTRK fusion-positive cancers, including those with resistance mutations.
  • B31 displays favorable in vitro and in vivo pharmacokinetic profiles.
Keywords:
AnticancerDrug resistanceIndazoleNTRK gene fusionTRK inhibitors

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