Discovery of the selective and efficacious inhibitors of FLT3 mutations

  • Eur J Med Chem. 2018 Jul 15;155:303-315. doi: 10.1016/j.ejmech.2018.06.010.
Yanle Zhi  1 ,  Baoquan Li  2 ,  Chao Yao  2 ,  Hongmei Li  2 ,  Puzhou Chen  2 ,  Jiyin Bao  2 ,  Tianren Qin  3 ,  Yue Wang  2 ,  Tao Lu  4 ,  Shuai Lu  5
Affiliations
  • 1. School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 2. School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 3. School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 4. School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 5. School of Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 29894944 DOI: 10.1016/j.ejmech.2018.06.010
Abstract

Fms-like tyrosine kinase 3 (FLT3) is among the most frequently mutated protein in acute myeloid leukemia (AML), which has been confirmed as an important drug target for AML chemotherapy. Starting from the lead compound LT-106-175, a series of 1-H-pyrazole-3-carboxamide derivatives were synthesized to improve the FLT3 inhibitory potency and selectivity. Among them, compound 50 was identified as a highly potent and selective FLT3 Inhibitor (IC50 = 0.213 nM), which showed equal activities against various mutants of FLT3 including FLT3 (ITD)-D835V and FLT3 (ITD)-F691L that is resistant to quizartinib. Compound 50 also exhibited efficacy against the human AML cell line MV4-11 (IC50 = 16.1 nM) harboring FLT3-ITD mutants. Inversely, compound 50 displayed no cytotoxicity to FLT3-independent cells, and the biochemical analyses showed that its effects were related to the inhibition of FLT3 signal pathways. Additionally, compound 50 induced Apoptosis in MV4-11 cell as demonstrated by flow cytometry. Moreover, compound 50 showed enhanced metabolic stability. Altogether, it was concluded that compound 50 could be a promising FLT3 Inhibitor for further developing therapeutic remedy of AML.

Keywords
AML; Acute myeloid; FLT3; FMS-Like tyrosine kinase 3 inhibitors; Leukemia.
Products