对临床 USP1 抑制剂 KSQ-4279 作用机制的结构和生化见解。
Structural and Biochemical Insights into the Mechanism of Action of the Clinical USP1 Inhibitor, KSQ-4279.
发表日期：2024 Aug 27
作者：
Martin Luke Rennie, Mehmet Gundogdu, Connor Arkinson, Steven Liness, Sheelagh Frame, Helen Walden
来源：
Protein & Cell
摘要：
DNA 损伤会触发细胞信号级联反应，从而介导修复。这种信号传导在癌症中经常失调。介导这种信号传导的蛋白质是治疗干预的潜在目标。泛素特异性蛋白酶 1 (USP1) 就是这样的靶标之一，小分子抑制剂已进入临床试验。在这里，我们使用生化测定和冷冻电子显微镜 (cryo-EM) 研究临床 USP1 抑制剂 KSQ-4279 (RO7623066)，并将其与成熟的工具化合物 ML323 进行比较。我们发现 KSQ-4279 与 ML323 结合到 USP1 的相同神秘位点，但以略有不同的方式破坏蛋白质结构。抑制剂结合可显着提高 USP1 的热稳定性，这可能是通过抑制剂填充 USP1 中的疏水性隧道状口袋来介导的。我们的结果有助于在分子水平上理解 USP1 抑制剂的作用机制。
DNA damage triggers cell signaling cascades that mediate repair. This signaling is frequently dysregulated in cancers. The proteins that mediate this signaling are potential targets for therapeutic intervention. Ubiquitin-specific protease 1 (USP1) is one such target, with small-molecule inhibitors already in clinical trials. Here, we use biochemical assays and cryo-electron microscopy (cryo-EM) to study the clinical USP1 inhibitor, KSQ-4279 (RO7623066), and compare this to the well-established tool compound, ML323. We find that KSQ-4279 binds to the same cryptic site of USP1 as ML323 but disrupts the protein structure in subtly different ways. Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel-like pocket in USP1. Our results contribute to the understanding of the mechanism of action of USP1 inhibitors at the molecular level.