Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders

Abstract

Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes - including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 - reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.

Fig. 1. Mechanisms of action of phosphatase-targeted drugs.

a,b, Orthosteric inhibitors bind to the phosphatase active site. a, Competitive inhibitors compete with substrate for binding to the phosphatase. b, Uncompetitive inhibitors bind to a phosphatase–substrate complex, preventing completion of catalysis. c, Oxidizing protein tyrosine phosphatase (PTP) inhibitors lead to oxidation of the PTP catalytic Cys. d, Irreversible inhibitors render the phosphatase inactive by covalently modifying the active site. e, Allosteric inhibitors induce or stabilize a catalytically unfavourable conformation of the phosphatase. f, Protein–protein interaction inhibitors disrupt or prevent complex formation between a phosphatase and its binding partner. g, Protein serine/threonine phosphatases (PSPs) can be inhibited by targeting specific regulatory subunits. h, PSPs can be activated by molecules that stabilize specific holoenzyme complexes. i, Phosphatases can be targeted by decoy biologics (targeting the extracellular region of receptor PTPs (RPTPs) or an intracellular region) or through antibodies. j, Proteolysis-targeting chimera (PROTAC) molecules target the phosphatase for degradation by bringing it into close proximity with an E3 ubiquitin ligase. CDC25, cell division cycle 25; EYA2, eyes absent 2; LMPTP, low-molecular-weight PTP; mAb, monoclonal antibody; PRL, phosphatase of regenerating liver; SET, su(var)3-9, enhancer of zeste, trithorax; SHP2, SH2 domain-containing PTP 2; STEP, striatum-enriched PTP; TC-PTP, T cell PTP; VE-PTP, vascular endothelial PTP; WIP1, wild-type p53-induced phosphatase 1.

Fig. 2. Regulation of SHP2 in tumour immunotherapy.

a, SH2 domain-containing PTP 2 (SHP2) is regulated by an auto-inhibited intramolecular mechanism. In the open conformation, the catalytic domain of SHP2 remains accessible for interaction with substrate. In the closed or inactive conformation, the N-SH2 domain blocks access to the catalytic site, rendering SHP2 inactive. SHP1 undergoes a similar regulation mechanism. b,c, Models for the PD1–SHP2 interaction. b, Two-step activation model. Before PD1 engagement on T cells, SHP2 resides in the auto-inhibited closed conformation. PDL1 binding recruits SHP2 to the phosphorylated immunoreceptor tyrosine-based switch motif (ITSM). Phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM) unfolds SHP2 into its active conformation. c, Dimerization model. SHP2 induces PD1 dimerization through N-SH2 and C-SH2 binding to the phospho-ITSM on two distinct PD1 molecules. TCR, T cell receptor.