Discovery of a First-in-Class Covalent Allosteric SHP1 Inhibitor with Immunotherapeutic Activity

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Src homology 2 domain-containing phosphatase 1 (SHP1) is a critical regulator of immune inhibitory signals.
• SHP1 dysregulation is implicated in various cancers, making it a target for immunotherapy.
• Existing SHP1 inhibitors face challenges due to the enzyme's active site chemistry.

Purpose of the Study:

• To discover and characterize a novel, first-in-class SHP1 inhibitor.
• To explore a new allosteric mechanism for SHP1 inhibition.
• To evaluate the therapeutic potential of SHP1 inhibition in cancer models.

Main Methods:

• Covalent fragment screening and multiparameter optimization were employed.
• A phenyl chloroacetamide-based covalent allosteric inhibitor, M029, was identified.
• In vitro assays, cellular target engagement studies, and in vivo cancer models were utilized.

Main Results:

• M029 covalently binds to Cys480, a cryptic site distinct from the active site, revealing a novel allosteric inhibition mechanism.
• M029 demonstrated high selectivity for SHP1 and robust cellular engagement.
• Orally administered M029 suppressed tumor progression in a syngeneic model by enhancing natural killer and CD8+ T cell activity and reducing T cell exhaustion.

Conclusions:

• A ligandable cysteine residue (Cys480) can be targeted for allosteric SHP1 inhibition, overcoming previous pharmacologic challenges.
• Small-molecule SHP1 inhibition represents a promising strategy for developing novel cancer immunotherapies.