Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China; Medicinal Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Pharmacol Ther. 2019 Oct;202:1-17. doi: 10.1016/j.pharmthera.2019.06.007. Epub 2019 Jun 22.
Ras, whose mutants are present in approximately 30% of human tumours, is one of the most important oncogenes. Drugging Ras is thus regarded as the quest for the Holy Grail in cancer therapeutics development. Despite more than three decades of efforts, drug discovery targeting Ras constantly fails, rendering Ras undruggable, due to its smooth surface and picomolar affinity towards guanosine substrates. The most frequently mutated isoform of Ras is K-Ras, accounting for >85% of Ras-driven cancers, and one majority of them is the G12C mutation. Recent advances in structural biology shed light on drugging Ras, and one of the cutting-edge breakthroughs is the design of covalent G12C-specific inhibitors targeting the mutated cysteine. This type of inhibitor can be classified into substrate-competitive orthosteric inhibitors and non-competitive allosteric inhibitors. They display improved selectivity and enhanced potency due to their G12-specific and irreversible covalent binding nature. Thus, they represent a new hope for revolutionizing the conventional characterization of Ras as "undruggable" and pave a promising avenue for further drug discovery. Here, we provide comprehensive structural and medicinal chemical insights into K-Ras covalent inhibitors specific for the G12C mutant. We first present an in-depth analysis of the conformations of the inhibitor binding pockets. Then, all the latest covalent ligands selectively inhibiting K-Ras are reviewed. Finally, we examine the current challenges faced by this new class of anti-Ras inhibitors.
Ras 是一种重要的癌基因，其突变体存在于约 30%的人类肿瘤中。因此，抑制 Ras 被视为癌症治疗药物开发中的圣杯。尽管经过三十多年的努力，针对 Ras 的药物发现不断失败，使得 Ras 成为不可成药的靶点，这是由于其光滑的表面和皮摩尔级对鸟嘌呤核苷底物的亲和力。Ras 最常突变的同工型是 K-Ras，占 Ras 驱动癌症的>85%，其中大多数是 G12C 突变。结构生物学的最新进展为 Ras 药物研发提供了线索，其中一个前沿突破是设计针对突变半胱氨酸的共价 G12C 特异性抑制剂。这种抑制剂可分为底物竞争性的正位抑制剂和非竞争性的变构抑制剂。由于其 G12 特异性和不可逆的共价结合性质，它们显示出更好的选择性和增强的效力。因此，它们为彻底改变 Ras“不可成药”的传统特征带来了新的希望，并为进一步的药物发现铺平了一条有前途的道路。在这里，我们提供了针对 G12C 突变体的 K-Ras 共价抑制剂的全面结构和药物化学见解。我们首先对抑制剂结合口袋的构象进行了深入分析。然后，综述了所有最新的选择性抑制 K-Ras 的共价配体。最后，我们考察了这一新类抗 Ras 抑制剂所面临的当前挑战。
