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

Research output: Contribution to journalArticle

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 separating 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.
LanguageEnglish
Pages145-154
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume79
Early online date30 Apr 2018
DOIs
StatusPublished - 1 Sep 2018

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Acyl Coenzyme A
Enzyme activity
Coenzyme A
Assays
Esters
Derivatives
Substrates
Pharmaceutical Preparations

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Structure-activity relationships of rationally designed AMACR 1A inhibitors. / Jevglevskis, Maksims; Lee, Guat Ling; Nathubhai, Amit; Petrova, Yoana; James, Tony; Threadgill, Michael; Woodman, Timothy; Lloyd, Matthew.

In: Bioorganic and Medicinal Chemistry, Vol. 79, 01.09.2018, p. 145-154.

Research output: Contribution to journalArticle

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