KAHA ligation as a platform for the rapid discovery of Protein Tyrosine phosphatase 1B (PTP1B) inhibitors

  • Bioorg Chem. 2025 Jan:154:108028. doi: 10.1016/j.bioorg.2024.108028.
Jing Tian  1 ,  Sijia Tan  2 ,  Liqian Gao  2 ,  Lakshminarayanan Rajamani  3 ,  Rajavel Srinivasan  4
Affiliations
  • 1. School of Pharmaceutical Science and Technology (SPST), Tianjin University, Tianjin 300072, PR China; Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai Minzu University, Xining 810007, PR China.
  • 2. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University and Shenzhen Campus of SunYat-sen University, Shenzhen 518107, PR China.
  • 3. Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
  • 4. School of Pharmaceutical Science and Technology (SPST), Tianjin University, Tianjin 300072, PR China; Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
PMID: 39673878 DOI: 10.1016/j.bioorg.2024.108028
Abstract

We have successfully designed and assembled a 66-member library of Protein tyrosine phosphatases (PTP) inhibitor candidates using α-ketoacid-hydroxylamine (KAHA) ligation. Subsequent in situ enzymatic screening revealed a potent hit (IC50 = 1.67 μM) against PTP1B, which displayed 6.8- to 50-fold selectivity over Other phosphatases.

Keywords
Chemoselective; Fragment-based library assembly; KAHA ligation; PTP1B inhibitors; Selective inhibitors.
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