The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1R,2S)-2-(3((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a Potent, Orally Active Antitumor Agent
The Discovery of Polo-Like Kinase 4 Inhibitors: Identification of (1R,2S)-2-(3((E)-4-(((cis)-2,6-Dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (CFI-400945) as a Potent, Orally Active Antitumor Agent
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DOI：
10.1021/jm5005336
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发表时间：
2015-01-08
影响因子：
7.3
通讯作者：
Pauls, Henry W.
中科院分区：
文献类型：
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作者：
Sampson, Peter B.;Liu, Yong;Pauls, Henry W.
我们实验室以前的出版物介绍了Polo样激酶4（PLK 4）的新型抑制剂，PLK 4是一种被鉴定为癌症治疗潜在靶点的有丝分裂激酶。对有效和选择性PLK 4抑制剂的研究产生了（E）-3-（（1H-吲唑-6-基）亚甲基）二氢吲哚-2-酮，其被生物电子等排的2-（1H-吲唑-6-基）螺[环丙烷-1，3 ′-二氢吲哚]-2 ′-酮取代，例如，3.后一种支架赋予改进的药物样性质，并包含两个立体中心。这项工作报告了一种新的一锅双S（N）2置换反应的发现，用于立体选择性安装所需的不对称中心，并证实了最有效的立体异构体的立体化学，例如，44.后续工作的关键是优化具有强效癌细胞生长抑制活性的纳摩尔PLK 4抑制剂的口服暴露。在小鼠肿瘤生长模型中研究了在啮齿动物和犬中具有上级效力和药代动力学性质的化合物的短列表。我们的结论与鉴定的化合物48（指定的CFI-400945）作为一种新的临床候选癌症治疗。
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search for potent and selective PLK4 inhibitors yielded (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3.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 S(N)2 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.