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

Jisheng Liu; Yuting Wang; Chen Chen; Zhengchao Tu; Sihua Zhu; Fengtao Zhou; Hongfei Si; Canhui Zheng; Zhang Zhang; Qian Cai

doi:10.1021/acsmedchemlett.0c00216

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

ACS Med Chem Lett. 2020 Jul 27;11(8):1567-1572. doi: 10.1021/acsmedchemlett.0c00216. eCollection 2020 Aug 13.

Authors

Jisheng Liu¹, Yuting Wang¹, Chen Chen¹, Zhengchao Tu^{1

2}, Sihua Zhu¹, Fengtao Zhou¹, Hongfei Si¹, Canhui Zheng³, Zhang Zhang¹, Qian Cai¹

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China.
² Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
³ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.

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.