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

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

  • Eur J Med Chem. 2025 Feb 5:283:117129. doi: 10.1016/j.ejmech.2024.117129.
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

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
  • 2 James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA; Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: zhang-zy@purdue.edu.
PMID: 39693863 DOI: 10.1016/j.ejmech.2024.117129
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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