Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors

Kazutomo Kinoshita; Yoshiyuki Ono; Takashi Emura; Kohsuke Asoh; Noriyuki Furuichi; Toshiya Ito; Hatsuo Kawada; Shota Tanaka; Kenji Morikami; Toshiyuki Tsukaguchi; Hiroshi Sakamoto; Takuo Tsukuda; Nobuhiro Oikawa

doi:10.1016/j.bmcl.2011.04.020

Discovery of novel tetracyclic compounds as anaplastic lymphoma kinase inhibitors

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3788-93. doi: 10.1016/j.bmcl.2011.04.020. Epub 2011 Apr 22.

Authors

Kazutomo Kinoshita¹, Yoshiyuki Ono, Takashi Emura, Kohsuke Asoh, Noriyuki Furuichi, Toshiya Ito, Hatsuo Kawada, Shota Tanaka, Kenji Morikami, Toshiyuki Tsukaguchi, Hiroshi Sakamoto, Takuo Tsukuda, Nobuhiro Oikawa

Affiliation

¹ Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., Kamakura, Kanagawa, Japan. kinoshitakzt@chugai-pharm.co.jp

PMID: 21561771
DOI: 10.1016/j.bmcl.2011.04.020

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.

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Disease Models, Animal
Drug Discovery*
Enzyme Activation / drug effects
Humans
Inhibitory Concentration 50
Mice
Molecular Structure
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Tetracyclines / chemical synthesis*
Tetracyclines / chemistry
Tetracyclines / pharmacology

Substances

Antineoplastic Agents
Tetracyclines
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases