Synthesis of ponatinib analogues as novel inhibitors of leukemia stem cells

Future Med Chem. 2022 May;14(9):623-645. doi: 10.4155/fmc-2022-0038. Epub 2022 Mar 25.

Abstract

Aim: To synthesize new analogues of ponatinib and evaluate anti-leukemia cells and cytotoxicity. Methodology & results: The inhibitory activity of compounds 13a and 13c against K562 and HL60 cells was comparable to that of ponatinib (IC50 = 0.74, 0.88 vs 0.64 nM and 0.59, 0.77 vs 0.39 nM, respectively). Compounds 13a and 40b were 34- and 77-fold more potent than ponatinib against KG1a cells (IC50 = 0.091 and 0040 vs 3.6 μM, respectively). Compounds 13a, 13c and 40b also decreased the Abl protein level in the K562 cells, inhibited colony formation in MCF-7 cells and inhibited cell migration in B16BL6 cells. Compound 13a showed low cytotoxicity in 293 cells. Conclusion: Compound 13a was the best lead compound.

Keywords: 1,2,3-triazole; 1,3,4-oxadiazole; cell wound scratch assay; leukemia cells; plate cloning test; ponatinib analogues; trifluoromethyl.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents*
  • Humans
  • Imidazoles
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive* / metabolism
  • Leukemia, Myeloid, Acute*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridazines* / pharmacology
  • Pyridazines* / therapeutic use
  • Stem Cells

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridazines
  • ponatinib