2. Academic Validation
  3. High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer's Disease and Cancer

High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer's Disease and Cancer

  • ACS Chem Biol. 2025 Jun 18. doi: 10.1021/acschembio.5c00110.
Laura Aitken 1,  Gemma Baillie 2,  Andrew Pannifer 3,  Angus Morrison 2,  Louise L Major 4,  Magnus S Alphey 4,  Ritika Sethi 5,  Martin Timmerman 6,  John Robinson 2,  Jennifer Riley 7,  Yoko Shishikura 7,  Lizbe Koekemoer 8,  Frank Von Delft 8,  Helma Rutjes 6,  Kevin D Read 7,  Philip S Jones 2,  Stuart P McElroy 2,  Terry K Smith 1 4,  Frank J Gunn-Moore 4
Affiliations

Affiliations

  • 1 University of St. Andrews School of Chemistry, Biomolecular Sciences Building, North Haugh, St. Andrews KY16 9TF, U.K.
  • 2 BioAscent Discovery Ltd, Bo'Ness Road, Newhouse, Lanarkshire ML1 5UH, U.K.
  • 3 Excientia, Oxford Science Park, The Schrödinger Building, Oxford OX4 4GE, U.K.
  • 4 Biomedical Science Research Complex, University of St. Andrews School of Biology, North Haugh, St. Andrews KY16 9ST, U.K.
  • 5 Glaxo Smith Kline Biologicals, rue de l'Institut 89, 1330 Rixensart, Belgium.
  • 6 European Lead Factory, Pivot Park-Banting Building (RE600), Kloosterstraat 9, 5349 AB Oss, The Netherlands.
  • 7 Wellcome Centre of Anti-infectives Research, Drug Discovery Unit, University of Dundee School of Life Sciences, Dow Street, Dundee DD1 5EH, U.K.
  • 8 University of Oxford Centre for Medicines Discovery, Old Road Campus Research Building, Oxford OX3 7FZ, U.K.
PMID: 40530895 DOI: 10.1021/acschembio.5c00110
Abstract

In this study, the first industrial-scale high-throughput screening of nearly 350,000 drug-like molecules targeting the enzyme 17β-HSD10, a promising therapeutic target for Alzheimer's disease and cancers, is presented. Two novel series of potent 17β-HSD10 inhibitors that demonstrate low nanomolar potency against both the enzyme and in vivo cellular assays with minimal cytotoxicity were identified. These inhibitors were characterized further through a series of assays demonstrating ligand-protein interactions and co-crystallography, revealing un-/non-competitive inhibition with respect to the cofactor NADH, unlike previously published inhibitors. This work significantly advances the development of 17β-HSD10-targeting therapeutics, offering new potential leads for treating Alzheimer's disease and cancers.

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