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.
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Acknowledgements
The authors were supported by grants R01AI148073, R01HL151306, R01AR066053, R01DK106233, R01HL152717 and R01AI070544 to N.B. and R21CA245621 to S.M.S. from the NIH, and Pathway to Stop Diabetes Grant 1-15-INI-13 to S.M.S. from the American Diabetes Association.
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Glossary
- Dimerization model
-
A model that depicts the interaction between SHP2 and PD1, in which SHP2 induces PD1 dimerization through N-SH2 and C-SH2 binding to phosphorylated immunoreceptor tyrosine-based switch motifs on two PD1 molecules.
- Nucleophilic substrate attack during catalysis
-
Covalent bond formation resulting from attack by an enzyme nucleophile on a substrate electrophile. Dephosphorylation by PTPs involves nucleophilic attack on the substrate phosphate by the catalytic Cys or His, forming a phospho-enzyme intermediate and releasing the dephosphorylated substrate. An active-site Asp serves as an acid, donating a proton to the tyrosyl group. The Asp (Glu in some PTPs) acts as a base to deprotonate a water molecule, which acts as a nucleophile to hydrolyse the phospho-enzyme intermediate.
- Orthosteric targeting
-
Development of modulators that target the enzyme active site.
- OT-I T cell
-
CD8+ T cell that carries a transgenic T cell receptor that recognizes ovalbumin peptide residues 257–264.
- OT-I–OVA mouse system
-
The OT-I mouse model bears a transgenic T cell receptor expressed on CD8+ T cells designed to recognize MHC class I-restricted ovalbumin (OVA) peptide residues 257–264. Transplantation of T cells from the OT-I mouse into mice bearing this fragment of OVA results in immune destruction of these cells.
- Two-step activation model
-
A model that depicts the activation of SHP2 by binding to PD1, in which T cell PD1 ligand binding recruits SHP2 to phosphorylated PD1 immunoreceptor tyrosine-based switch motif, and further PD1 phosphorylation on the immunoreceptor tyrosine-based inhibitory motif is needed to unfold SHP2 into its active conformation and propagate inhibitory PD1 signalling.
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Stanford, S.M., Bottini, N. Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders. Nat Rev Drug Discov 22, 273–294 (2023). https://doi.org/10.1038/s41573-022-00618-w
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DOI: https://doi.org/10.1038/s41573-022-00618-w