Potent dialkyl substrate-product analogue inhibitors and inactivators of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis by rational design

Pal, M.; Easton, Nicole M.; Yaphe, Hannah; Bearne, Stephen L.

doi:10.1016/j.bioorg.2018.01.041

Cited by 9 publications

(16 citation statements)

References 48 publications

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“…Analogues of known inhibitors with modified 2-methylacyl-CoA moieties (4,(23)(24)(25)(26) were also examined. The results reveal a correlation between potency and lipophilicity of the inhibitors, con-sistent with observations on MCR inhibitors [35], the homologous en-zyme from M. tuberculosis.…”

Section: Introductionsupporting

confidence: 81%

“…the enzyme active site concentration is < 0.1 × the apparent Ki value (0.65 nM [32]). This rapidly reversible inhibition is significantly different behaviour to that observed for similar com-pounds (gem-carbamoyl inhibitors and N-decylcarbamoyl-CoA) with the highly homologous bacterial enzyme MCR, where time-dependent inactivation was observed [35]. The reasons for this difference in be-haviour are not entirely obvious.…”

Section: Evaluation Of Inhibitorscontrasting

confidence: 57%

“…The accommodation of these di-verse structures is thought to be a result of non-specific binding of the side-chain by hydrophobic interactions to a methionine-rich surface [8]. Consistent with this, the MCR gem- [31] and gem-carbamate [35] inhibitors show increased potency for compounds with more hydro-phobic alkyl side-chains. Consequently, we were interested to in-vestigate whether inhibitor potency was related to the lipophilicity of the inhibitor side-chain.…”

Section: Influence Of the Side-chain Lipophilicity On Inhibitor Potencymentioning

confidence: 83%

“…In most cases, only one or a few examples of each in-hibitor type has been evaluated, and no systematic SAR study has been performed. Initial SAR studies have been carried out on reversible [31] and irreversible [35] inhibitors of MCR (the M. tuberculosis homologue). In addition, different research groups have used different assays during their studies, making it difficult to compare results directly.…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, AMACR has attracted considerable interest as a prostate cancer biomarker [1,2,27] and drug target [25,[28][29][30][31]. However, the lack of a convenient assay to measure AMACR activity [32,33] has severely hampered the development of AMACR inhibitors as new chemotherapeutic drugs against cancers that over-express AMACR, and consequently only a few rationally designed inhibitors of AMACR [28][29][30]34] or MCR [31,35] (M. tuberculosis homologue) have been reported. No systematic study of AMACR Scheme 1.…”

Section: Introductionmentioning

confidence: 99%

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Structure-activity relationships of rationally designed AMACR 1A inhibitors

Yevglevskis

Lee

Nathubhai

et al. 2018

Bioorganic Chemistry

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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 = 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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