Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802).
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. kinoshitakzt@chugai-pharm.co.jp
Kazutomo
K
Kinoshita
Kohsuke
K
Asoh
Noriyuki
N
Furuichi
Toshiya
T
Ito
Hatsuo
H
Kawada
Sousuke
S
Hara
Jun
J
Ohwada
Takuho
T
Miyagi
Takamitsu
T
Kobayashi
Kenji
K
Takanashi
Toshiyuki
T
Tsukaguchi
Hiroshi
H
Sakamoto
Takuo
T
Tsukuda
Nobuhiro
N
Oikawa
D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D000882:Haplorhini; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases