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

Jing Tian; Sijia Tan; Liqian Gao; Lakshminarayanan Rajamani; Rajavel Srinivasan

doi:10.1016/j.bioorg.2024.108028

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

Bioorg Chem. 2024 Dec 9:154:108028. doi: 10.1016/j.bioorg.2024.108028. Online ahead of print.

Authors

Jing Tian¹, Sijia Tan², Liqian Gao², Lakshminarayanan Rajamani³, Rajavel Srinivasan⁴

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.