Projects per year
Abstract
α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the ‘racemisation’ reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure–activity relationship study has been performed. This paper describes the first structure–activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated. AMACR was potently inhibited (IC 50 = 400–750 nM) by ibuprofenoyl-CoA and derivatives. Potency was positively correlated with inhibitor lipophilicity. AMACR was also inhibited by straight-chain and branched-chain acyl-CoA esters, with potency positively correlating with inhibitor lipophilicity. 2-Methyldecanoyl-CoAs were ca. 3-fold more potent inhibitors than decanoyl-CoA, demonstrating the importance of the 2-methyl group for effective inhibition. Elimination substrates and compounds with modified acyl-CoA cores were also investigated, and shown to be potent inhibitors. These results are the first to demonstrate structure–activity relationships of rational AMACR inhibitors and that potency can be predicted by acyl-CoA lipophilicity. The study also demonstrates the utility of the colorimetric assay for thorough inhibitor characterisation.
Original language | English |
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Pages (from-to) | 145-154 |
Number of pages | 10 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 79 |
Early online date | 30 Apr 2018 |
DOIs | |
Publication status | Published - 1 Sept 2018 |
Keywords
- Drug lipophilicity
- Enzyme inhibitors
- Rational drug design
- Structure-activity relationships
- α-Methylacyl-CoA racemase (AMACR, P504S)
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Drug Discovery
- Organic Chemistry
Fingerprint
Dive into the research topics of 'Structure-activity relationships of rationally designed AMACR 1A inhibitors'. Together they form a unique fingerprint.Projects
- 2 Finished
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AMACR Targeted Drugs for Treating Advance Prostate Cancer
Lloyd, M. (PI), James, T. (CoI), Jevglevskis, M. (CoI), Nathubhai, A. (CoI), Threadgill, M. (CoI) & Woodman, T. (CoI)
1/02/15 → 30/07/18
Project: UK charity
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AMACR Targeted Drugs for Treating Advance Prostate Cancer
James, T. (PI)
1/02/15 → 31/01/18
Project: UK charity
Equipment
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Avance III 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (9West)
Material and Chemical Characterisation (MC2)Facility/equipment: Equipment
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Avance III 500 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (9West)
Material and Chemical Characterisation (MC2)Facility/equipment: Equipment
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MC2-Mass Spectrometry (MS)
Material and Chemical Characterisation (MC2)Facility/equipment: Technology type