Abstract
Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.
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The Discovery of Polo-Like Kinase 4 Inhibitors: Design and Optimization of Spiro[cyclopropane-1,3′[3H]indol]-2′(1′H)-ones as Orally Bioavailable Antitumor Agents
Peter B. Sampson, Yong Liu, Narendra Kumar Patel, Miklos Feher, Bryan Forrest, Sze-Wan Li, Louise Edwards, Radoslaw Laufer, Yunhui Lang, Fuqiang Ban, Donald E. Awrey, Guodong Mao, Olga Plotnikova, Genie Leung, Richard Hodgson, Jacqueline Mason, Xin Wei, Reza Kiarash, Erin Green, Wei Qiu, Nickolay Y. Chirgadze, Tak W. Mak, Guohua Pan, and Henry W. PaulsJournal of Medicinal Chemistry
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