Jassim Brenson A, Bai Yunpeng, Qu Zihan, Sander Conrad J, Lin Jianping, Miao Jinmin, Zhang Zhong-Yin
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.
Eur J Med Chem. 2025 Feb 5;283:117129. doi: 10.1016/j.ejmech.2024.117129. Epub 2024 Dec 6.
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.
蛋白酪氨酸磷酸酶非受体22型（PTPN22）位于T细胞受体（TCR）下游，通过使关键效应蛋白（如LCK、Zap70和TCR的细胞内区域）去磷酸化来减弱T细胞信号传导。最近的证据表明，PTPN22是提高癌症免疫治疗疗效的一个令人兴奋的靶点。我们结合晶体结构分析、合成、匹配分子对分析以及生化和细胞实验，对基于苯并呋喃水杨酸的正构PTPN22抑制剂8b进行了结构优化。在此，我们报告了构效关系研究、基于8b-PTPN22共晶体结构的先导优化以及顶级类似物的细胞评估。值得注意的是，我们的努力得到了化合物8b-19，它与母体8b相比，是一种基本等效的骨架，具有优异的同工酶选择性、改善的水溶性和显著增强的细胞疗效。该化合物可作为进一步优化靶向PTPN22的免疫疗法的先导物，或作为化学探针，用于探究PTPN22与细胞免疫调节之间的其他联系。
