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
  • 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: [email protected].
  • 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: [email protected].
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.