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Structure-activity relationships of rationally designed AMACR 1A inhibitors

Yevglevskis, M., Lee, G. L, Nathubhai, Amit, Petrova, Y.D., James, T.D., Threadgill, M.D., Woodman, T.J and Lloyd, M.D. (2018) Structure-activity relationships of rationally designed AMACR 1A inhibitors. BIOORGANIC CHEMISTRY, 79. pp. 145-154. ISSN 0045-2068

Item Type: Article


alpha-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 (IC50= 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.

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Depositing User: Amit Nathubhai


Item ID: 9783
Identification Number:
ISSN: 0045-2068
Official URL:

Users with ORCIDS

ORCID for Amit Nathubhai: ORCID iD

Catalogue record

Date Deposited: 10 Aug 2018 07:29
Last Modified: 18 Dec 2019 16:07


Author: Amit Nathubhai ORCID iD
Author: M. Yevglevskis
Author: G. L Lee
Author: Y.D. Petrova
Author: T.D. James
Author: M.D. Threadgill
Author: T.J Woodman
Author: M.D. Lloyd

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences


Sciences > Chemistry

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