Discovery and Evaluation of Active Site-Directed, Potent, and Selective Sulfophenyl Acetic Amide-Based Inhibitors for the Laforin Phosphatase
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 <b>9c</b> displayed a <i>K</i><sub><i>i</i></sub> 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.
Authors
- Lindsey R. Conroy (ORCID: https://orcid.org/0000-0003-4593-0896)
- Aaron D. Krabill (ORCID: https://orcid.org/0000-0001-9265-4201)
- Yiming Miao (ORCID: https://orcid.org/0000-0003-0316-5970)
- Rongjun He (ORCID: https://orcid.org/0000-0001-9093-5165)
- Frederick Nguele Meke (ORCID: https://orcid.org/0000-0001-8542-0343)
- Ramon C. Sun (ORCID: https://orcid.org/0000-0002-3009-1850)
- Ronald C. Bruntz (ORCID: https://orcid.org/0009-0005-5104-9837)
- Matthew S. Gentry (ORCID: https://orcid.org/0000-0001-5253-9049)
- Jianping Lin (ORCID: https://orcid.org/0000-0001-6974-0072)
- Zihan Qu (ORCID: https://orcid.org/0009-0004-8446-8459)
- Benjamin Ayodipupo Babalola (ORCID: https://orcid.org/0000-0001-8188-9056)
- Yunpeng Bai (ORCID: https://orcid.org/0000-0002-5879-3555)
- Brenson A. Jassim
- Zhong‐Yin Zhang (ORCID: https://orcid.org/0000-0001-5527-7910)
- Jiajun Dong (ORCID: https://orcid.org/0000-0002-6901-5070)
- Li Wu (ORCID: https://orcid.org/0000-0002-7898-7517)
Institutions
- Allen Institute for Brain Science (US)
- University of Kentucky (US)
- Purdue University West Lafayette (US)
- University of Florida (US)
- Tarpo (Czechia) (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02580
- Primary Topic
- Glycogen Storage Diseases and Myoclonus
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute on Aging
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke