基于蛋白质组学的研究发现了针对程序性细胞死亡蛋白2（PDCD2）的首创化学探针。
Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2).
发表日期：2023 Sep 01
作者：
Wenzhi Ji, Woong Sub Byun, Wenchao Lu, Xijun Zhu, Katherine A Donovan, Brendan Dwyer, Jianwei Che, Linjie Yuan, Xianmixinuer Abulaiti, Steven M Corsello, Eric S Fischer, Tinghu Zhang, Nathanael Schiander Gray
来源：
Cell Death & Disease
摘要：
化学探针是理解生物系统和确认潜在生物医学靶点的关键工具。程序化细胞死亡2(PDCD2)是B细胞淋巴瘤2(Bcl-2)蛋白家族的成员，这些蛋白是调控细胞凋亡的重要调节因子。我们在这里报道了10e的发现和表征，这是一种首创的小分子PDCD2降解剂。我们在化学蛋白质组学方法的帮助下偶然地发现了PDCD2降解剂，与传统方法不同，传统方法是从已知针对所需蛋白的结合配体开始制作双价降解剂。通过使用10e作为药理学探针，我们证明PDCD2通过调节T淋巴母细胞系的细胞周期进程，发挥着细胞生长的重要调控作用。我们的研究为研究PDCD2功能提供了有用的药理学探针，并突出了使用化学蛋白质组学方法发现选择性小分子降解剂的非预期靶点的重要性。© 2023 Wiley-VCH GmbH.
Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first-in-class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.© 2023 Wiley-VCH GmbH.