化学
部分
奎宁
立体化学
加合物
激酶
组合化学
选择性
生物化学
有机化学
催化作用
作者
Osamu Kurasawa,T. Miyazaki,Misaki Homma,Yuya Oguro,Takashi Imada,Noriko Uchiyama,Kenichi Iwai,Yukiko Yamamoto,Momoko Ohori,Hideto Hara,Hiroshi Sugimoto,Kentaro Iwata,R.J. Skene,Isaac Hoffman,Akihiro Ohashi,Toshiyuki Nomura,Nobuo Cho
标识
DOI:10.1021/acs.jmedchem.9b01427
摘要
In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.
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