Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
ERATO (Exploratory Research for Advanced Technology, JST), Sanbancho, Chiyodaku, Tokyo, 102-0075, Japan.
J Am Chem Soc. 2021 Mar 31;143(12):4766-4774. doi: 10.1021/jacs.1c00703. Epub 2021 Mar 18.
Protein-protein interactions (PPIs) intimately govern various biological processes and disease states and therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors for PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible inhibitors of the human double minute 2 (HDM2)/p53 PPI, which employ a reactive -acyl--alkyl sulfonamide (NASA) group as a warhead. Mass-based analysis successfully revealed the kinetics of covalent inhibition and the modification sites on HDM2 to be the N-terminal α-amine and Tyr67, both rarely seen in traditional covalent inhibitors. Finally, we demonstrated prolonged p53-pathway activation and more effective induction of the p53-mediated cell death in comparison to a noncovalent inhibitor. This study highlights the potential of the NASA warhead as a versatile electrophile for the covalent inhibition of PPIs and opens new avenues for the rational design of potent covalent PPI inhibitors.
蛋白质-蛋白质相互作用 (PPIs) 密切调控着各种生物过程和疾病状态，因此被认为是小分子药物发现极具吸引力的治疗靶标。然而，开发高效的 PPI 抑制剂极具挑战性，成功的临床案例有限。在此，我们报告了人双微体 2 (HDM2)/p53 PPI 的不可逆抑制剂，其采用反应性酰基-烷基磺酰胺 (NASA) 基团作为弹头。基于质量的分析成功揭示了共价抑制的动力学和 HDM2 的修饰位点为 N 端α-胺和 Tyr67，这两个修饰位点在传统共价抑制剂中很少见。最后，与非共价抑制剂相比，我们证明了它能更有效地延长 p53 通路的激活并诱导 p53 介导的细胞死亡。本研究强调了 NASA 弹头作为一种通用亲电试剂用于共价抑制 PPI 的潜力，并为设计强效共价 PPI 抑制剂开辟了新途径。
