Synthesis of ponatinib analogues as novel inhibitors of leukemia stem cells.

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.

• Authors: Lei Wang, Xiu-Juan Zhao, Chuang Hua, Hai-Xiang Wu, Cui-Gai Bai, Yue Chen
• Journal: Future medicinal chemistry (Future Med Chem) Vol. 14 Issue 9 Pg. 623-645 (05 2022) ISSN: 1756-8927 [Electronic] England
• PMID: 35332794 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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