Mapping the Chemical Space of Active‐Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases**

Abstract

Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phos-phatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases.

Design, Construction, and Validation of a Yeast-Displayed Chemically Expanded Antibody Library

“…The vector to express the catalytic domain of PTP1B (pET-28 His-TEV-PTP1B-cat) 67 was a generous gift from the Shah Lab at Columbia University. The PTP1B expression plasmid was transformed into chemically competent BL21(DE3) cells (generously gifted by the Nair Lab at Tufts University) and streaked on LB plates containing 50 µg/mL kanamycin.…”