Journal
CHEMMEDCHEM
Volume 11, Issue 15, Pages 1587-1595Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201600224
Keywords
anticancer activity; benzothiazoles; ethylpiperazine; multikinase inhibitors
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Funding
- Korea Institute of Science and Technology (KIST) Institutional Program [2E26650, 2E26663]
- Ministry of Science, ICT & Future Planning, Republic of Korea [2E26650] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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