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 affe...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2012-02, Vol.20 (3), p.1271-1280
Hauptverfasser:	Kinoshita, Kazutomo, Asoh, Kohsuke, Furuichi, Noriyuki, Ito, Toshiya, Kawada, Hatsuo, Hara, Sousuke, Ohwada, Jun, Miyagi, Takuho, Kobayashi, Takamitsu, Takanashi, Kenji, Tsukaguchi, Toshiyuki, Sakamoto, Hiroshi, Tsukuda, Takuo, Oikawa, Nobuhiro
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral ALK Anaplastic lymphoma kinase Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Biological and medical sciences Carcinoma, Non-Small-Cell Lung - drug therapy Cell Line, Tumor CH5424802 Haplorhini Humans Kinase inhibitors Lung Neoplasms - drug therapy Medical sciences Neoplasms - drug therapy Pharmacology. Drug treatments Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Rats Rats, Sprague-Dawley Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - metabolism
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Zusammenfassung:	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.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2011.12.021