直接靶向 KRAS 的小分子抑制剂：从结构见解到基于机制的设计。
Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.
机构信息
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA.
出版信息
Nat Rev Drug Discov. 2016 Nov;15(11):771-785. doi: 10.1038/nrd.2016.139. Epub 2016 Jul 29.
PMID:27469033
Abstract
KRAS is the most frequently mutated oncogene in human cancer. In addition to holding this distinction, unsuccessful attempts to target this protein have led to the characterization of RAS as 'undruggable'. However, recent advances in technology and novel approaches to drug discovery have renewed hope that a direct KRAS inhibitor may be on the horizon. In this Review, we provide an in-depth analysis of the structure, dynamics, mutational activation and inactivation, and signalling mechanisms of RAS. From this perspective, we then consider potential mechanisms of action for effective RAS inhibitors. Finally, we examine each of the many recent reports of direct RAS inhibitors and discuss promising avenues for further development.
摘要
KRAS 是人类癌症中最常发生突变的致癌基因。除了具有这一区别外，靶向这种蛋白质的不成功尝试导致 RAS 被描述为“不可成药”。然而，技术的最新进展和新药发现的新方法为直接 KRAS 抑制剂的出现带来了新的希望。在这篇综述中，我们对 RAS 的结构、动力学、突变激活和失活以及信号转导机制进行了深入分析。从这个角度出发，我们随后考虑了有效 RAS 抑制剂的潜在作用机制。最后，我们检查了最近关于直接 RAS 抑制剂的许多报告，并讨论了进一步开发的有前途的途径。
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