Structure-activity relationship studies and design of a PTPN22 inhibitor with enhanced isozyme selectivity and cellular efficacy.

ABSTRACT: Protein tyrosine phosphatase non-receptor type 22 (PTPN22) lies downstream of the T cell receptor (TCR) and attenuates T cell signaling by dephosphorylating key effector proteins such as LCK, Zap70, and the intracellular region of the TCR. Recent evidence implicates PTPN22 as an exciting target for enabling immunotherapeutic efficacy against cancer. We carried out structural optimization of a benzofuran salicylic acid-based orthosteric PTPN22 inhibitor 8b, using a combination of crystal structure analysis, synthesis, matched molecular pairs analysis, and biochemical and cell-based assays. Herein, we report structure-activity relationship studies, lead optimization based on the 8b-PTPN22 co-crystal structure, and cellular evaluation of the top analog. Notably, our efforts yielded compound 8

SUBMITTER: Jassim BA 

PROVIDER: S-EPMC11709133 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature