Noji Satoru, Seki Noriyoshi, Maeba Takaki, Sakai Takayuki, Watanabe Eiichi, Maeda Katsuya, Fukushima Kyoko, Noguchi Toru, Ogawa Kazuya, Toyonaga Yukiyo, Negoro Tamotsu, Kawasaki Hisashi, Shiozaki Makoto
Chemical Research Laboratories, Biological Pharmacological Research Laboratories, and Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc. , 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
ACS Med Chem Lett. 2016 Aug 3;7(10):919-923. doi: 10.1021/acsmedchemlett.6b00232. eCollection 2016 Oct 13.
In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy. PI4KIIIα is one of four mammalian phosphatidylinositol-4 kinases and has recently drawn significant attention as an emerging target for hepatitis C virus (HCV) treatment. In this letter, a novel "head-to-tail" approach to discover a diverse set of PI4KIIIα inhibitors is reported. We believe this method will generate distinct core scaffolds, a rational strategy to circumvent potential risks in general kinase programs.
在典型的激酶抑制剂研发项目中，首先会选择一种对铰链区具有最佳亲和力且具有优先特异性的结合剂，随后对其核心模块上的附属取代基进行微调。这种方法的一个缺点是，如果发现了一个关键缺陷，那么仅关注单一化学类型可能会危及该系列中的所有类似物。因此，尽管很少有遵循这种策略的实例，但对构效关系（SARs）进行早期评估可以减轻一系列多种化合物中不可预见的结果。PI4KIIIα是四种哺乳动物磷脂酰肌醇-4激酶之一，最近作为丙型肝炎病毒（HCV）治疗的一个新兴靶点受到了广泛关注。在这封信中，报道了一种用于发现多种PI4KIIIα抑制剂的新颖“头对尾”方法。我们相信这种方法将产生不同的核心支架，这是一种规避一般激酶项目中潜在风险的合理策略。
