Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad-Spectrum Antiproliferative Activity

作者：El Damasy Ashraf Kareem; Cho Nam Chul; Nam Ghilsoo; Pae Ae Nim; Keum Gyochang^*

来源：ChemMedChem, 2016, 11(15): 1587-1595.

DOI：10.1002/cmdc.201600224

• anticancer activity
• benzothiazoles
• ethylpiperazine
• multikinase inhibitors

Herein we report the discovery of compound 6 [KST016366; 4-((2-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)benzo[d]thiazol-6-yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A. Invitro anticancer evaluation of 6 showed substantial broad-spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI(50) values of 51.4 and 19nm against leukemia K-562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar-level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC50 values of 0.82, 3.81, and 53nm toward Tie2, TrkA, and ABL-1 (wild-type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable invivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.

• 出版日期2016-8-5