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Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad‐Spectrum Antiproliferative Activity
Author(s) -
ElDamasy Ashraf Kareem,
Cho NamChul,
Nam Ghilsoo,
Pae Ae Nim,
Keum Gyochang
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600224
Subject(s) - kinase , chemistry , benzothiazole , in vivo , ic50 , tyrosine kinase , pharmacology , angiogenesis , cell culture , in vitro , pharmacokinetics , cancer research , biochemistry , biology , signal transduction , genetics , microbiology and biotechnology
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 . In vitro 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 19 n m 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 IC 50 values of 0.82, 3.81, and 53 n m toward Tie2, TrkA, and ABL‐1 (wild‐type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.