9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors

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• 作者：Kazutomo Kinoshita ; Takamitsu Kobayashi ; Kohsuke Asoh ; Noriyuki Furuichi ; Toshiya Ito ; Hatsuo Kawada ; Sousuke Hara ; Jun Ohwada ; Kazuo Hattori ; Takuho Miyagi ; Woo-Sang Hong ; Min-Jeong Park ; Kenji Takanashi ; Toshiyuki Tsukaguchi ; Hiroshi Sakamoto ; Takuo Tsukuda ; Nobuhiro Oikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 22, 2011
• 年：2011
• 卷：54
• 期：18
• 页码：6286-6294
• 全文大小：986K
• 年卷期：v.54,no.18(September 22, 2011)
• ISSN：1520-4804

文摘

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 E₀ 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 IC₅₀ value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC₅₀ 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.