Structure-activity relationships of rationally designed AMACR 1A inhibitors

Maksims Yevglevskis, Guat L Lee, Amit Nathubhai, Yoana D Petrova, Tony D James, Michael D Threadgill, Timothy J Woodman, Matthew D Lloyd

Research output: Contribution to JournalArticlepeer-review


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 (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.
Original languageEnglish
Pages (from-to)145-154
Number of pages10
JournalBioorganic Chemistry
Early online date30 Apr 2018
Publication statusPublished - 1 Sept 2018

Bibliographical note

Copyright © 2018 Elsevier Inc. All rights reserved.


  • Acyl Coenzyme A/chemical synthesis
  • Drug Design
  • Enzyme Assays
  • Enzyme Inhibitors/chemical synthesis
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Isoenzymes/antagonists & inhibitors
  • Molecular Structure
  • Racemases and Epimerases/antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship


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