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Updated: Jun 4, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Structure-activity relationship studies and design of a PTPN22 inhibitor with enhanced isozyme selectivity and
Brenson A Jassim1, Yunpeng Bai1, Zihan Qu2
1Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
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.
Insights
Researchers optimized a PTPN22 inhibitor for cancer immunotherapy. The new compound, 8b-19, shows improved properties and efficacy, serving as a potential lead for novel immunotherapies.
Area of Science:
- Immunology
- Medicinal Chemistry
- Structural Biology
Background:
- Protein tyrosine phosphatase non-receptor type 22 (PTPN22) regulates T cell receptor (TCR) signaling.
- PTPN22 dephosphorylates key signaling proteins, impacting T cell activation.
- PTPN22 is a promising target for enhancing cancer immunotherapies.
Purpose of the Study:
- To structurally optimize a benzofuran salicylic acid-based PTPN22 inhibitor (compound 8b).
- To develop novel PTPN22 inhibitors for cancer immunotherapy.
- To identify potent and selective PTPN22 modulators for further research.
Main Methods:
- Co-crystal structure analysis of PTPN22 inhibitor 8b.
- Structure-activity relationship (SAR) studies.
- Synthesis and biochemical/cell-based assays of novel analogs.
- Matched molecular pairs analysis.
Main Results:
- Structural optimization yielded compound 8b-19, a potent PTPN22 inhibitor.
- Compound 8b-19 demonstrated equipotent inhibition to 8b but with enhanced isozyme selectivity.
- Improved aqueous solubility and significantly enhanced cellular efficacy were observed for 8b-19.
- The lead compound 8b-19 showed superior properties compared to the parent compound 8b.
Conclusions:
- Compound 8b-19 represents a promising lead for PTPN22-targeting cancer immunotherapies.
- The optimized inhibitor may serve as a chemical probe to investigate PTPN22's role in immunomodulation.
- Further optimization could lead to novel therapeutic strategies for cancer treatment.
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