Protein tyrosine phosphatase inactivation by electrophilic tyrosine modification

TL;DR

This paper introduces a new covalent inhibitor that inactivates a specific protein tyrosine phosphatase by modifying a functional tyrosine, offering a novel approach for targeting these enzymes.

Contribution

The study presents a tyrosine-reactive covalent inhibitor with molecular glue activity through a ligand-induced protein tethering mechanism.

Findings

DML189 covalently modifies SHP2 at Y279, inducing reversible disulfide tethering and monomer loss.

Ligand-induced protein tethering (LIPT) was observed uniquely on SHP2, not on PTP1B, LYP, or SHP1.

Crosslinking mass spectrometry revealed regulatory cysteine tethering events after DML189 modification.

Abstract

Covalent protein tyrosine phosphatase (PTP) inhibitors principally target the catalytic cysteine, which is highly conserved and presents challenges for achieving selectivity across the PTP family. Here, we identified a tyrosine-reactive covalent inhibitor for SHP2 (DML189) with secondary molecular glue activity via a ligand induced protein tethering (LIPT) mechanism. We detected ligand binding at Y279, which is in proximity to the catalytic cysteine on SHP2 and has known functional and pathogenic properties. Covalent SHP2 modification by DML189 induced reversible disulfide tethering and monomer loss that was not observed to the same extent on PTP1B, LYP, or SHP1. Crosslinking mass spectrometry detected unique tethering events involving regulatory cysteines after DML189 modification on SHP2. Together, we discovered a tyrosine reactive inhibitor that targets functional sites on SHP2 and exhibits molecular glue activity through LIPT.

Here, we develop covalent inhibitors that inactivate protein tyrosine phosphatases (PTPs) via electrophilic modification of functional tyrosines.

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