Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations

J Med Chem. 2024 Dec 26;67(24):21752-21780. doi: 10.1021/acs.jmedchem.4c00529. Epub 2024 Sep 11.

Abstract

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Bridged-Ring Compounds
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Mutation*
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Pyrimidines
  • Structure-Activity Relationship
  • fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3* / genetics
  • fms-Like Tyrosine Kinase 3* / metabolism

Substances

  • fms-Like Tyrosine Kinase 3
  • FLT3 protein, human
  • Protein Kinase Inhibitors
  • Antineoplastic Agents
  • 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
  • Bridged-Ring Compounds
  • Pyrimidines