In vitro assay development and HTS of small molecule human ABAD/17β-HSD10 inhibitors as therapeutics in Alzheimer’s Disease

Laura Aitken; Gemma Baillie; Andrew Pannifer; Angus Morrison; Philip S. Jones; Terry K. Smith; Stuart P. McElroy; Frank J. Gunn-Moore

doi:10.1177/2472555217697964

In vitro assay development and HTS of small molecule human ABAD/17β-HSD10 inhibitors as therapeutics in Alzheimer’s Disease

Laura Aitken, Gemma Baillie, Andrew Pannifer, Angus Morrison, Philip S. Jones, Terry K. Smith, Stuart P. McElroy, Frank J. Gunn-Moore

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

Abstract

A major hallmark of Alzheimer’s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

Original language	English
Pages (from-to)	676-685
Number of pages	11
Journal	SLAS Discovery
Volume	22
Issue number	6
Early online date	17 Mar 2017
DOIs	https://doi.org/10.1177/2472555217697964
Publication status	Published - Jul 2017

Keywords

Enzyme assays or enzyme kinetics
Neurodegenerative diseases
Pharmacology: ligand binding
Receptor binding
Ultra-high throughput screening

UN SDGs

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

Access to Document

10.1177/2472555217697964

Aitken_2017_SLASD_AssayDevelopment_AAM
© 2017 Society for Laboratory Automation and Screening. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at: https://doi.org/10.1177/247255521769796
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Cite this

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title = "In vitro assay development and HTS of small molecule human ABAD/17β-HSD10 inhibitors as therapeutics in Alzheimer{\textquoteright}s Disease",

abstract = "A major hallmark of Alzheimer{\textquoteright}s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.",

keywords = "Enzyme assays or enzyme kinetics, Neurodegenerative diseases, Pharmacology: ligand binding, Receptor binding, Ultra-high throughput screening",

author = "Laura Aitken and Gemma Baillie and Andrew Pannifer and Angus Morrison and Jones, {Philip S.} and Smith, {Terry K.} and McElroy, {Stuart P.} and Gunn-Moore, {Frank J.}",

note = "This research was funded by the Scottish Universities Life Science Alliance (SULSA) assay development fund. This research was also kindly supported by The Rosetrees Trust and The Alzheimer{\textquoteright}s Society, specifically The Barcopel Foundation, and partly funded by the MSD Scottish Life Sciences fund. As part of an ongoing contribution to Scottish life sciences, MSD Limited, a global health care leader, has given substantial monetary funding to the Scottish Funding Council for distribution via SULSA to develop and deliver a high-quality drug discovery research and training program.",

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AU - Morrison, Angus

AU - Jones, Philip S.

AU - Smith, Terry K.

AU - McElroy, Stuart P.

AU - Gunn-Moore, Frank J.

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N2 - A major hallmark of Alzheimer’s disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development. Here we have established a high-throughput screening platform for the identification of modulators to the ABAD enzyme. A pilot screen with a total of 6759 compounds from the NIH Clinical Collections (NCC) and SelleckChem libraries and a selection of compounds from the BioAscent diversity collection have allowed validation and robustness to be optimized. The pilot screen revealed 16 potential inhibitors in the low µM range against ABAD with favorable physicochemical properties for blood-brain barrier penetration.

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In vitro assay development and HTS of small molecule human ABAD/17β-HSD10 inhibitors as therapeutics in Alzheimer’s Disease

Abstract

Keywords

UN SDGs

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Novel Drugs for Alzheimer's disease: Novel Drugs for Alzheimer's disease

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In vitro assay development and HTS of small molecule human ABAD/17β-HSD10 inhibitors as therapeutics in Alzheimer’s Disease

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Novel Drugs for Alzheimer's disease: Novel Drugs for Alzheimer's disease

Cite this