Proteomics‐Based Discovery of First‐in‐Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2)

Abstract 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.