title: 9-substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as highly selective and potent anaplastic lymphoma kinase inhibitors.
abstract: 9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. kinoshitakzt@chugai-pharm.co.jp
authors.forename: Kazutomo
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kobayashi
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: Sousuke
authors.initials: S
authors.lastname: Hara
authors.forename: Jun
authors.initials: J
authors.lastname: Ohwada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hattori
authors.forename: Takuho
authors.initials: T
authors.lastname: Miyagi
authors.forename: Woo-Sang
authors.initials: WS
authors.lastname: Hong
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Park
authors.forename: Kenji
authors.initials: K
authors.lastname: Takanashi
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* / Q000493:pharmacokinetics / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C562235:9-ethyl-6,6-dimethyl-8-(4-oxetan-3-ylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo(b)carbazole-3-carbonitrile; D000970:Antineoplastic Agents; D002227:Carbazoles; D010879:Piperazines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases