Protein Tyrosine Phosphatase Nonreceptor Type 22 (PTPN22) is a cytosolic PTP expressed exclusively in hematopoietic cells and is a key negative regulator of T cell signaling. As such, PTPN22 has emerged as a promising systemic and translatable cancer immunotherapy target. Pharmacological abrogation of PTPN22 by previously discovered inhibitor L-1 led to reduced tumor growth in multiple tumor models and synergized with anti-PD1 treatment. Despite L-1’s promising and robust in vivo efficacy, its potency (IC<sub>50</sub> 1.4 ± 0.2µM), selectivity, solubility, and pharmacokinetics warrant further improvement for clinical application. Herein, we report the design, synthesis, and biological evaluation of L-1 derivatives with improved potency, selectivity, aqueous solubility, and cellular efficacy. Ongoing efforts are focused on measuring in vivo PK properties, modifying the quinolone core of L-107-8, and testing these compounds in tumor xenograft models in mice.

Optimization of small molecule PTPN22 inhibitors for immunotherapy

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