title: 3-Cyano-6-(5-methyl-3-pyrazoloamino) pyridines (Part 2): A dual inhibitor of Aurora kinase and tubulin polymerization.
abstract: A new class of a dual inhibitor of Aurora kinase and tubulin polymerization was created by introducing various substituted phenoxyethylamino or pyridyloxyethylamino groups to the 2-position of 3-cyano-4-methyl-6-(5-methyl-3-pyrazoloamino)-pyridine. Compound 3g exhibited Aurora kinase inhibition, excellent protein kinase selectivity to Aurora kinase in comparison with 66 other kinases, inhibition of phosphorylation of Ser10 of histone H3 as an Aurora kinase inhibitor, inhibition of tubulin polymerization in vitro, good cell membrane permeability, and a good PK profile. Therefore compound 3g was effective in some antitumor mouse models at a dose of 30mg/kgpoqd.
authors.affiliation: R&D, Marketing & Business Planning Division, CXS Corporation, 22 Yamashita-cho, Naka-ku, Yokohama 231-0023, Japan. Electronic address: sakura-saku1103@rondo.ocn.ne.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Morioka
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D014404:Tubulin; D064127:Aurora Kinases
keywords: Anti-cancer reagent; Aurora kinase inhibitor; Tubulin polymerization inhibitor