A Potent and Selective Quinolone-Based PTPN22 Inhibitor with Improved Immunotherapeutic Activity.

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a cytosolic enzyme expressed primarily in hematopoietic cells that negatively regulates T cell signaling and antitumor immune response. Genetic and pharmacological studies have demonstrated that PTPN22 is a systemic immunotherapy target that can enhance T cell activation and function when abrogated, resulting in reduced tumor burden. Building on our previously reported PTPN22 inhibitor, L-1, we present the design, synthesis, and biological evaluation of a novel series of quinolone-3-carboxylic acid-based inhibitors. In addition to gaining new insights into the structure-activity relationship of this scaffold, compound L-32 displays improved potency, selectivity, and cellular efficacy compared to L-1. Notably, L-32 exhibits a more favorable pharmacokinetic profile and drug properties, including oral bioavailability. Finally, L-32 is superior to L-1 in reducing MC38 tumor growth in vivo by promoting robust antitumor immunity, thus offering a promising lead molecule for the development of novel anticancer agents targeting PTPN22.