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Comprehensive structure-activity-relationship of azaindoles as highly potent FLT3 inhibitors

Sebastian H Grimm1, Berend Gagestein1, Jordi F Keijzer1

  • 1Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.

Bioorganic & Medicinal Chemistry
|January 22, 2019
PubMed

Insights

Researchers identified novel azaindole compounds as potent inhibitors of Fms-like tyrosine kinase 3 (FLT3) for treating acute myeloid leukemia (AML). These findings offer new chemical strategies against drug-resistant FLT3 mutations in AML patients.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) presents aggressive progression and poor prognosis.
  • Fms-like tyrosine kinase 3 (FLT3) mutations are key drivers in a subset of AML cases.
  • Acquired drug resistance necessitates the development of novel therapeutic agents.

Purpose of the Study:

  • To discover and characterize novel inhibitors targeting Fms-like tyrosine kinase 3 (FLT3).
  • To explore the structure-activity relationships (SAR) of isoquinolinesulfonamide analogs as FLT3 inhibitors.
  • To identify new chemical entities effective against drug-resistant FLT3 mutations.

Main Methods:

  • Synthesis and evaluation of isoquinolinesulfonamide analogs.
  • Structure-activity relationship (SAR) analysis, including matched molecular pair analysis.
  • Structure-based modeling utilizing the FLT3 crystal structure.

Main Results:

  • Identified novel azaindole derivatives as potent FLT3 inhibitors with sub-nanomolar activity.
  • Observed a binding mode for new inhibitors inconsistent with the known binding of H-89 to PKA.
  • Structure-based modeling suggested an alternative, flipped binding orientation for the azaindole inhibitors.

Conclusions:

  • Azaindoles represent a promising new class of FLT3 inhibitors for AML treatment.
  • The identified inhibitors may overcome resistance mechanisms associated with existing FLT3 therapies.
  • Further investigation into the novel binding mode could guide the design of next-generation FLT3 inhibitors.
Keywords:
Acute myeloid leukemia (AML)Fms-like tyrosine kinase 3 (FLT3)H-89 analogsInhibitors

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