Mapping the chemical space of active-site targeted covalent ligands for protein tyrosine phosphatases

06 March 2023, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

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 phosphatases. 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.

Keywords

tyrosine phosphatase
covalent inhibition
cysteine labeling
enzymes
inhibitors
structure-activity relationships
protein structures

Supplementary materials

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Supporting Information
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Supplementary figures S1-S13, sequences of protein constructs, synthesis and characterization of compounds, and Table S1, containing structures of all compounds.
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Table S2
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Residual activity of PTPs after treatment with diverse phenyl-substituted warheads.
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Table S3
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Residual activity of PTPs after treatment with chloroacetamide-substituted scaffolds.
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Table S4
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IC50 values for inhibition of PTPs by chloroacetamides.
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Table S5
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Second-order rate constants for reactions between chloroacetamides and TNB2+.
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