title: Evaluation of a multi-kinase inhibitor KRC-108 as an anti-tumor agent in vitro and in vivo.
abstract: Kinases have been studied as potential cancer targets because they play important roles in the cellular signaling of tumors. A number of small molecules targeting kinases are prescribed in clinics and many kinase inhibitors are being evaluated in the clinical phase. Previously, we discovered a series of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors. One of the compounds, KRC-108, has been evaluated as an anti-cancer agent in vitro and in vivo. A kinase panel assay exhibited that KRC-108 is a potent inhibitor of Ron, Flt3 and TrkA as well as c-Met. Moreover, KRC-108 inhibited oncogenic c-Met M1250T and Y1230D more strongly than wild type c-Met. The anti-proliferative activity of KRC-108 was measured by performing a cytotoxicity assay on a panel of cancer cell lines. The GI(50) values (i.e., 50% inhibition of cell growth) for KRC-108 ranged from 0.01 to 4.22 μM for these cancer cell lines. KRC-108 was also effective for the inhibition of tumor growth in human HT29 colorectal cancer and NCI-H441 lung cancer xenograft models in athymic BALB/c nu/nu mice. This molecule should serve as a useful lead for inhibitors targeting kinases and may lead to new therapeutics for the treatment of cancer.
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-600, Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Han
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Mi-Ok
authors.initials: MO
authors.lastname: Lee
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kang
authors.forename: Hyuk-Jin
authors.initials: HJ
authors.lastname: Cha
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Ryu
authors.forename: Heejung
authors.initials: H
authors.lastname: Jung
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Koh
authors.forename: Jongkook
authors.initials: J
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001583:Benzoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; C572621:KRC-108; D047428:Protein Kinase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D051941:fms-Like Tyrosine Kinase 3