title: Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors.
abstract: Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivatives as potent ALK inhibitors. Among them, compound 27 showed strong cytotoxicity against KARPAS-299 with an IC(50) value of 21 nM and significant antitumor efficacy in ALK fusion-positive blood and solid cancer xenograft models in mice without body weight loss.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., Kamakura, Kanagawa, Japan. kinoshitakzt@chugai-pharm.co.jp
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ono
authors.forename: Takashi
authors.initials: T
authors.lastname: Emura
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Asoh
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Furuichi
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ito
authors.forename: Hatsuo
authors.initials: H
authors.lastname: Kawada
authors.forename: Shota
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsukaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Takuo
authors.initials: T
authors.lastname: Tsukuda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Oikawa
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013754:Tetracyclines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases