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

Laura Aitken; Gemma Baillie; Andrew Pannifer; Angus Morrison; Louise L. Major; Magnus S. Alphey; Ritika Sethi; Martin Timmerman; John Robinson; Jennifer Riley; Yoko Shishikura; Lizbe Koekemoer; Frank Von Delft; Helma Rutjes; Kevin D. Read; Philip S. Jones; Stuart P. McElroy; Terry K. Smith; Frank J. Gunn-Moore

doi:10.1021/acschembio.5c00110

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

Laura Aitken
, Gemma Baillie
, Andrew Pannifer
, Angus Morrison
, Louise L. Major
, Magnus S. Alphey
, Ritika Sethi
, Martin Timmerman
, John Robinson
, Jennifer Riley
, Yoko Shishikura
, Lizbe Koekemoer
, Frank Von Delft
, Helma Rutjes
, Kevin D. Read
, Philip S. Jones
, Stuart P. McElroy
, Terry K. Smith
, Frank J. Gunn-Moore (Lead / Corresponding author)

Drug Discovery Unit

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

57 Downloads (Pure)

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.

Original language	English
Pages (from-to)	1544-1559
Number of pages	16
Journal	ACS Chemical Biology
Volume	20
Issue number	7
Early online date	18 Jun 2025
DOIs	https://doi.org/10.1021/acschembio.5c00110
Publication status	Published - 18 Jul 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/acschembio.5c00110Licence: CC BY

Final published versionFinal published version, 11 MBLicence: CC BY

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Aitken, L., Baillie, G., Pannifer, A., Morrison, A., Major, L. L., Alphey, M. S., Sethi, R., Timmerman, M., Robinson, J., Riley, J., Shishikura, Y., Koekemoer, L., Von Delft, F., Rutjes, H., Read, K. D., Jones, P. S., McElroy, S. P., Smith, T. K., & Gunn-Moore, F. J. (2025). High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer’s Disease and Cancer. ACS Chemical Biology, 20(7), 1544-1559. https://doi.org/10.1021/acschembio.5c00110

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title = "High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer{\textquoteright}s Disease and Cancer",

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{\textquoteright}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{\textquoteright}s disease and cancers.",

author = "Laura Aitken and Gemma Baillie and Andrew Pannifer and Angus Morrison and Major, \{Louise L.\} and Alphey, \{Magnus S.\} and Ritika Sethi and Martin Timmerman and John Robinson and Jennifer Riley and Yoko Shishikura and Lizbe Koekemoer and \{Von Delft\}, Frank and Helma Rutjes and Read, \{Kevin D.\} and Jones, \{Philip S.\} and McElroy, \{Stuart P.\} and Smith, \{Terry K.\} and Gunn-Moore, \{Frank J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

year = "2025",

month = jul,

day = "18",

doi = "10.1021/acschembio.5c00110",

language = "English",

volume = "20",

pages = "1544--1559",

journal = "ACS Chemical Biology",

issn = "1554-8929",

publisher = "American Chemical Society",

number = "7",

}

Aitken, L, Baillie, G, Pannifer, A, Morrison, A, Major, LL, Alphey, MS, Sethi, R, Timmerman, M, Robinson, J, Riley, J , Shishikura, Y, Koekemoer, L, Von Delft, F, Rutjes, H, Read, KD, Jones, PS, McElroy, SP, Smith, TK & Gunn-Moore, FJ 2025, 'High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer’s Disease and Cancer', ACS Chemical Biology, vol. 20, no. 7, pp. 1544-1559. https://doi.org/10.1021/acschembio.5c00110

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T1 - High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer’s Disease and Cancer

AU - Aitken, Laura

AU - Baillie, Gemma

AU - Pannifer, Andrew

AU - Morrison, Angus

AU - Major, Louise L.

AU - Alphey, Magnus S.

AU - Sethi, Ritika

AU - Timmerman, Martin

AU - Robinson, John

AU - Riley, Jennifer

AU - Shishikura, Yoko

AU - Koekemoer, Lizbe

AU - Von Delft, Frank

AU - Rutjes, Helma

AU - Read, Kevin D.

AU - Jones, Philip S.

AU - McElroy, Stuart P.

AU - Smith, Terry K.

AU - Gunn-Moore, Frank J.

PY - 2025/7/18

Y1 - 2025/7/18

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AB - 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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SN - 1554-8929

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JF - ACS Chemical Biology

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

Abstract

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