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

Angew Chem Int Ed Engl. 2023 Sep 1:e202308292. doi: 10.1002/anie.202308292. Online ahead of print.ABSTRACTChemical 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.PMID:37658265 | DOI:10.1002/anie.202308292

Source: Angewandte Chemie - September 1, 2023 Category: Chemistry Authors: 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 Source Type: research