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

Xing-Dong Lin; Hui-Wen Yang; Shuang Ma; Wei-Wei Li; Chun-Hui Zhang; Wen-Jing Wang; Rong Xiang; Lin-Li Li; Sheng-Yong Yang

doi:10.1016/j.bmcl.2015.08.068

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. Epub 2015 Aug 28.

Authors

Xing-Dong Lin¹, Hui-Wen Yang¹, Shuang Ma¹, Wei-Wei Li¹, Chun-Hui Zhang¹, Wen-Jing Wang¹, Rong Xiang², Lin-Li Li³, Sheng-Yong Yang⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
HeLa Cells
Humans
Molecular Structure
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
fms-Like Tyrosine Kinase 3 / metabolism

Substances

6-(4-(3-(5-(tert-butyl)isoxazol- 3-yl)ureido)phenyl)-N-(3-(dimethylamino)propyl)imidazo(2,1-b)thiazole-3-carboxamide
Phenylurea Compounds
Protein Kinase Inhibitors
Thiazoles
FLT3 protein, human
fms-Like Tyrosine Kinase 3