Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy

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• 作者：Sze-Wan Li ; ^{swli@uhnresearch.ca" class="auth_mail" title="E-mail the corresponding author} ; Yong Liu ; Peter B. Sampson ; Narendra Kumar Patel ; Bryan T. Forrest ; Louise Edwards ; Radoslaw Laufer ; Miklos Feher ; Fuqiang Ban ; Donald E. Awrey ; Richard Hodgson ; Irina Beletskaya ; Guodong Mao ; Jacqueline M. Mason ; Xin Wei ; Xunyi Luo ; Reza Kiarash ; Erin Green ; Tak W. Mak ; Guohua Pan ; Henry W. Pauls ; ^{henry.pauls@cogeco.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Polo-like kinase 4 ; PLK4 inhibitors ; Spiro[cyclopropane-1 ; 3&prime ; -indolin]-2&prime ; -ones ; (1H-Indazol-6-yl)-methylene)indolin-2-ones ; Antitumor agent
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4625-4630
• 全文大小：2483 K

文摘

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein ‘directly-linked’ aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.