Structure-activity relationships of rationally designed AMACR 1A inhibitors

Maksims Jevglevskis, Guat Ling Lee, Amit Nathubhai, Yoana Petrova, Tony James, Michael Threadgill, Timothy Woodman, Matthew Lloyd

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


  • 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


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