Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
Lingang Laboratory, Shanghai, 20031, China.
Angew Chem Int Ed Engl. 2023 Oct 23;62(43):e202308292. doi: 10.1002/anie.202308292. Epub 2023 Sep 15.
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 10 e, a first-in-class small molecule degrader of PDCD2. We discovered this 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 10 e 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 the use of chemical proteomics to discover selective small molecule degraders of unanticipated targets.
化学探针是理解生物系统和鉴定潜在生物医学靶标的重要工具。程序性细胞死亡蛋白 2（PDCD2）是 B 细胞淋巴瘤 2（Bcl-2）家族蛋白的成员，是细胞凋亡的关键调节因子。在这里，我们报告了 10e 的发现和特征，这是一种针对 PDCD2 的首创小分子降解剂。我们使用化学蛋白质组学方法意外地发现了这种 PDCD2 降解剂，这与从针对目标蛋白的已知结合配体开始构建双价降解剂的传统方法形成对比。使用 10e 作为药理学探针，我们证明 PDCD2 通过调节 T 淋巴母细胞中细胞周期的进展，作为细胞生长的关键调节因子发挥作用。我们的工作为研究 PDCD2 功能提供了一个有用的药理学探针，并强调了使用化学蛋白质组学来发现针对意外靶标的选择性小分子降解剂。
