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. 2025 Feb 5:283:117129.
doi: 10.1016/j.ejmech.2024.117129. Epub 2024 Dec 6.

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

Brenson A Jassim  1 , Yunpeng Bai  1 , Zihan Qu  2 , Conrad J Sander  1 , Jianping Lin  1 , Jinmin Miao  1 , Zhong-Yin Zhang  3
Affiliations

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

Brenson A Jassim et al. Eur J Med Chem. .

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 8b-19, an essentially equipotent scaffold with superior isozyme selectivity, improved aqueous solubility, and significantly enhanced cellular efficacy compared to the parent 8b. This compound may serve as a lead for further optimization of PTPN22-targeting immunotherapies or as a chemical probe for interrogation for additional links between PTPN22 and immunomodulation in cells.

Keywords: Cancer immunotherapy; LYP; PTPN22; PTPN22 inhibitors.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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