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변웅섭Woong Sub Byun

Stanford University School of Medicine

Angew. Chem.-Int. Edit., Sep 01 2023 | https://doi.org/10.1002/anie.202308292 Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2)

Wenzhi Ji ^1#, Woong Sub Byun^1#, Wenchao Lu ¹, Xijun Zhu ¹, Katherine A Donovan ², Brendan Dwyer¹, Jianwei Che², Linjie Yuan ¹, Xianmixinuer Abulaiti ¹, Steven M Corsello¹, Eric S Fischer ², Tinghu Zhang^1*, Nathanael Schiander Gray^3*

¹Stanford Cancer Institute, Department of Chemical and Systems Biology, UNITED STATES.

²Dana-Farber Cancer Institute, Department of Cancer Biology, UNITED STATES.

³Stanford University School of Medicine, Chemical and Systems Biology, 290 Jane Stanford Way, 94305, Stanford, UNITED STATES.

^#W. Ji and W. S. Byun contributed equally to this work.

^*CORRESPONDING AUTHORS: Tinghu Zhang, Nathanael Schiander Gray

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 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.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-18)
연구진국외 연구진
분야 의약학 > 약학

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