KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea; Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
Cell Chem Biol. 2023 Nov 16;30(11):1414-1420.e5. doi: 10.1016/j.chembiol.2023.07.008. Epub 2023 Aug 10.
Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves an induced proximity between the cellular ubiquitin-conjugation machinery and a target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-like homology domain-containing protein 2 (KLHDC2), a substrate adapter protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of peptide-based ligands useful for this purpose.
化学诱导的蛋白质降解是一种用于扰乱细胞生物化学的强大策略。蛋白降解药物的主要作用机制涉及细胞泛素缀合机制与靶标之间的诱导接近。与传统的小分子酶抑制不同，靶向蛋白质降解可以从细胞中清除不需要的蛋白质。我们在这里展示了使用肽配体对 Kelch 样同源结构域蛋白 2 (KLHDC2)的应用，KLHDC2 是一种底物衔接蛋白，也是 cullin-2 (CUL2)泛素连接酶复合物的成员，用于靶向蛋白质降解。能够诱导 KLHDC2 与靶蛋白之间接近的基于肽的双价化合物会导致靶标因子的降解。这些化合物的细胞活性取决于 KLHDC2 的结合。这项工作证明了 KLHDC2 用于靶向蛋白质降解的实用性，并举例说明了用于该目的的基于肽的配体的合理设计策略。
