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
  • 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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