2. Academic Validation
  3. Discovery and Evaluation of Active Site-Directed, Potent, and Selective Sulfophenyl Acetic Amide-Based Inhibitors for the Laforin Phosphatase

Discovery and Evaluation of Active Site-Directed, Potent, and Selective Sulfophenyl Acetic Amide-Based Inhibitors for the Laforin Phosphatase

  • J Med Chem. 2025 May 8;68(9):9220-9240. doi: 10.1021/acs.jmedchem.4c02580.
Jianping Lin 1,  Rongjun He 1,  Zihan Qu 2,  Jiajun Dong 1,  Aaron D Krabill 1,  Li Wu 3,  Yunpeng Bai 1,  Lindsey R Conroy 4,  Ronald C Bruntz 5,  Yiming Miao 1,  Brenson A Jassim 1,  Benjamin Babalola 2,  Frederick Georges Bernard Nguele Meke 1,  Ramon Sun 6 7 8,  Matthew S Gentry 6 7,  Zhong-Yin Zhang 1 2 3
Affiliations

Affiliations

  • 1 Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2 The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3 Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4 Department of Neuroscience, University of Kentucky, Lexington, Kentucky 40506, United States.
  • 5 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506, United States.
  • 6 Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, United States.
  • 7 Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, Florida 32610, United States.
  • 8 McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, United States.
PMID: 40238926 DOI: 10.1021/acs.jmedchem.4c02580
Abstract

Lafora disease is a rare and fatal progressive myoclonus epilepsy characterized by the accumulation of insoluble glycogen deposits in the brain and peripheral tissues. Mutations in the gene encoding the glycogen Phosphatase laforin result in Lafora disease. Currently, there are no laforin-specific chemical probes, limiting our understanding of the roles of laforin in glycogen metabolism and Other cellular processes. Here, we identified sulfophenyl acetic amide (SPAA), as a novel nonhydrolyzable phosphotyrosine mimetic for laforin inhibition. Using fragment-based and scaffold-hopping strategies, we discovered several highly potent and selective active site-directed laforin inhibitors. Among them, compound 9c displayed a Ki value of 1.9 ± 0.2 nM and more than 8300-fold preference for laforin. Moreover, these inhibitors efficiently block laforin-mediated glucan dephosphorylation inside the cell and possess favorable pharmacokinetic properties in mice. These chemical probes will enable further investigation of the roles of laforin in normal physiological processes and in diseases.

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