High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer’s Disease and Cancer
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 <i>in vivo</i> 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.
Authors
- Louise L. Major (ORCID: https://orcid.org/0000-0001-5287-4488)
- Laura Aitken (ORCID: https://orcid.org/0000-0001-7259-4491)
- Frank J. Gunn‐Moore (ORCID: https://orcid.org/0000-0003-3422-3387)
- Kevin D. Read (ORCID: https://orcid.org/0000-0002-8536-0130)
- Martin Timmerman
- Andrew Pannifer (ORCID: https://orcid.org/0000-0003-0866-308X)
- L. Koekemoer (ORCID: https://orcid.org/0000-0001-9226-9127)
- F. von Delft (ORCID: https://orcid.org/0000-0003-0378-0017)
- M.S. Alphey
- Yoko Shishikura
- Angus J. Morrison (ORCID: https://orcid.org/0000-0003-2274-7140)
- Jennifer Riley
- John S. Robinson
- Philip S. Jones
- Terry Smith (ORCID: https://orcid.org/0000-0003-1994-2009)
- Ritika Sethi (ORCID: https://orcid.org/0000-0001-6015-7710)
- Stuart P. McElroy (ORCID: https://orcid.org/0000-0002-5182-2616)
- Gemma L. Baillie
- Helma Rutjes
Institutions
- University of St Andrews (GB)
- University of Dundee (GB)
- NHS Lanarkshire (GB)
- University of Oxford (GB)
- GlaxoSmithKline (Belgium) (BE)
- European Lead Factory (NL)
- Wellcome Centre for Anti-Infectives Research (GB)
- GlaxoSmithKline (Switzerland) (CH)
- Science Oxford (GB)
Publication Details
- Journal
- ACS Chemical Biology
- Published
- 2025-06-18
- DOI
- https://doi.org/10.1021/acschembio.5c00110
- Primary Topic
- Hormonal Regulation and Hypertension
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Society
- Rosetrees Trust
- European Lead Factory
- Medical Research Council
- Engineering and Physical Sciences Research Council