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Identification and Development of 1,4-Diaryl-1,2,3-triazolo-Based Ureas as Novel FLT3 Inhibitors.

ABSTRACT: A class of 1,4-diaryl-1,2,3-triazolo-based ureas were synthesized and developed as novel FLT3 inhibitors. The representative compound 28 strongly inhibited FLT3-ITD kinase (IC₅₀ = 32.8 nM) and isogenic BaF3-FLT3-ITD cell (GI₅₀ = 0.6 nM). It exhibited potent inhibition against FLT3-ITD positive MV4-11 (GI₅₀ = 3.0 nM) and MOLM-13 (GI₅₀ = 5.9 nM) cell lines and high selectivity over FLT3-WT cell lines. It also displayed good pharmacokinetics properties and demonstrated promising oral in vivo efficacy in a MV4-11 cell xenografted mouse model. It might be a potent lead compound for further development to treat FLT3-ITD driven acute myloid leukemia.

SUBMITTER: Liu J

PROVIDER: S-EPMC7430953 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Identification and Development of 1,4-Diaryl-1,2,3-triazolo-Based Ureas as Novel FLT3 Inhibitors.

Liu Jisheng J Wang Yuting Y Chen Chen C Tu Zhengchao Z Zhu Sihua S Zhou Fengtao F Si Hongfei H Zheng Canhui C Zhang Zhang Z Cai Qian Q

ACS medicinal chemistry letters 20200727 8

A class of 1,4-diaryl-1,2,3-triazolo-based ureas were synthesized and developed as novel FLT3 inhibitors. The representative compound 28 strongly inhibited FLT3-ITD kinase (IC50 = 32.8 nM) and isogenic BaF3-FLT3-ITD cell (GI50 = 0.6 nM). It exhibited potent inhibition against FLT3-ITD positive MV4-11 (GI50 = 3.0 nM) and MOLM-13 (GI50 = 5.9 nM) cell lines and high selectivity over FLT3-WT cell lines. It also displayed good pharmacokinetics proper ...[more]

PMID: 32832025

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