Hong-Rae Kim, David P Byun, Kalyani Thakur, Jennifer Ritchie, Yixin Xie, Ronald Holewinski, Kiall F Suazo, Mckayla Stevens, Hope Liechty, Ravichandra Tagirasa, Yihang Jing, Thorkell Andresson, Steven M Johnson, Euna Yoo
Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (SN Ar) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60)...
April 17, 2024: ACS Chemical Biology