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

Bioorganic & Medicinal Chemistry Letters
Xing-Dong LinSheng-Yong Yang

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.

References

Jan 17, 2003·Leukemia·H QuentmeierH G Drexler
Apr 2, 2004·Cell·Tony Hunter, Walter Eckhart
May 5, 2005·Blood·Martin S TallmanJacob M Rowe
Jul 14, 2010·Oncogene·E WeisbergJ D Griffin

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