title: Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad-Spectrum Antiproliferative Activity.
abstract: 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 GI50 values of 51.4 and 19 nm 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 53 nm 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.
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon, 305-350, Republic of Korea.|Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
authors.forename: Ashraf Kareem
authors.initials: AK
authors.lastname: El-Damasy
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea.
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Cho
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon, 305-350, Republic of Korea.
authors.forename: Ghilsoo
authors.initials: G
authors.lastname: Nam
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon, 305-350, Republic of Korea.
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
authors.affiliation: Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea. gkeum@kist.re.kr.|Department of Biological Chemistry, Korea University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon, 305-350, Republic of Korea. gkeum@kist.re.kr.
authors.forename: Gyochang
authors.identifier: 0000-0001-8767-8022
authors.initials: G
authors.lastname: Keum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000070819:Discoidin Domain Receptor 1 / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020917:Receptor, trkA / Q000737:chemistry; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; C000622622:KST016366; C000611485:NTRK1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; C000588866:KDR protein, human; D020917:Receptor, trkA; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: anticancer activity; benzothiazoles; ethylpiperazine; multikinase inhibitors