Discovery of Benzofuran-2-Carboxylic Acid Derivatives as Potent PTPRO Inhibitors with Oral Efficacy for Treatment of Inflammatory Bowel Disease

  • J Med Chem. 2026 May 14;69(9):11167-11191. doi: 10.1021/acs.jmedchem.6c00259.
Xiao Liang  1  2 ,  Xue Li  1 ,  Junxin Xue  1 ,  Huirui Wang  3 ,  Huajun Zhao  1 ,  Zhongcheng Zhao  1 ,  Xinying Yang  1 ,  Jintong Du  4 ,  Ting Dong  5 ,  Hao Fang  1 ,  Xuben Hou  1
Affiliations
  • 1. Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Shandong Basic Science Academic Special Zone/Research Center (Pharmacy), School of Pharmaceutical Sciences, Cheelo College of Medicine, Shandong University, Jinan 250012, Shandong, China.
  • 2. Department of Pharmacy, Qilu Hospital of Shandong University, Ji'nan 250012, Shandong, China.
  • 3. Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education) and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong University, Jinan 250012, China.
  • 4. Phase I Clinical Research Center, Shandong Cancer Hospital, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji'nan 250117, Shandong, China.
  • 5. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
PMID: 42046270 DOI: 10.1021/acs.jmedchem.6c00259
Abstract

Emerging evidence implicates PTPRO as a pivotal regulator in inflammatory bowel disease (IBD). Screening a benzofuran-2-carboxylic acid-based library identified a lead PTPRO inhibitor. Structure-guided optimization yielded compound 10j, a potent and selective PTPRO inhibitor (IC50 = 0.54 μM) that suppressed IL-6 via NF-κB pathway modulation in macrophages. Compound 10j exhibited favorable oral bioavailability and, in a murine DSS-induced colitis model, significantly attenuated disease severity, restored colon length, and suppressed IFN-γ and IL-2 levels. Further optimization produced 30k with enhanced potency (IC50 = 0.16 μM) and superior in vivo efficacy accompanied by an improved safety profile. This work establishes benzofuran-2-carboxylic acid derivatives as promising IBD therapeutics, providing a pharmacological tool for phosphatase-targeted immunomodulation.

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