2. Academic Validation
  3. Discovery of 6-phenylimidazo[2,1-b]thiazole derivatives as a new type of FLT3 inhibitors

Discovery of 6-phenylimidazo[2,1-b]thiazole derivatives as a new type of FLT3 inhibitors

  • Bioorg Med Chem Lett. 2015 Oct 15;25(20):4534-8. doi: 10.1016/j.bmcl.2015.08.068.
Xing-Dong Lin 1,  Hui-Wen Yang 1,  Shuang Ma 1,  Wei-Wei Li 1,  Chun-Hui Zhang 1,  Wen-Jing Wang 1,  Rong Xiang 2,  Lin-Li Li 3,  Sheng-Yong Yang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan 610041, China.
  • 2 Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin, China.
  • 3 West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: ysylilinli@sina.com.cn.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan 610041, China. Electronic address: yangsy@scu.edu.cn.
PMID: 26342867 DOI: 10.1016/j.bmcl.2015.08.068
Abstract

In this investigation, a series of 6-phenylimidazo[2,1-b]thiazole derivatives were synthesized. Structure-activity relationship (SAR) analysis of these compounds based on cellular assays led to the discovery of a number of compounds that showed potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell line MV4-11, but very weak or no activity against FLT3-independent human cervical Cancer cell line Hela. FLT3 kinase inhibition assays were then performed on the three most active compounds. Among these compounds, 6-(4-(3-(5-(tert-butyl)isoxazol- 3-yl)ureido)phenyl)-N-(3-(dimethylamino)propyl)imidazo[2,1-b]thiazole-3-carboxamide (19) exhibited the highest potency in both cellular (MV4-11, IC50: 0.002 μM) and enzymatic (FLT3, IC50: 0.022 μM) assays. Further in-depth in vitro anti-AML activity and mechanism of action studies were carried out on compound 19.

Keywords

6-Phenylimidazo[2,1-b]thiazole; Acute myeloid leukemia (AML); Anti-viability; FLT3; FLT3-ITD; MV4-11.

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