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

Abstract Src homology 2 domain‐containing phosphatase 1 (SHP1), encoded by PTPN6 , is a key intracellular mediator of inhibitory immune signals. SHP1 is garnering attention as a potential immunotherapeutic target since SHP1 deletion elicits strong antitumor activity by boosting both innate and adaptive immunity. Unfortunately, no quality SHP1 inhibitor exists to demonstrate its translatability owing to the challenges posed by the chemistry of the phosphatase active site. Herein, we describe the discovery of a first‐in‐class, phenyl chloroacetamide‐based covalent allosteric SHP1 inhibitor M029 through covalent fragment screening and multiparameter optimization. M029 inactivates SHP1 by covalently binding to a non‐conserved and cryptic Cys480 far away from the active site, thus uncovering a novel allosteric mechanism for SHP1 inhibition. In addition, M029 is highly selective for SHP1 and exhibits robust cellular target engagement. Importantly, M029 is orally active and blocks tumor progression in a syngeneic cancer model by activating natural killer cells and cytotoxic CD8 + T cells, along with reduced T cell exhaustion. Together, this study reveals a ligandable Cys that can be exploited for allosteric inhibition of SHP1, which has been refractory to targeted pharmacologic manipulation. The work also demonstrates small‐molecule SHP1 inhibition as a compelling approach for new cancer immunotherapy.