Structure-activity relationships of rationally designed AMACR 1A inhibitors
| Autor: | Guat Ling Lee, Maksims Yevglevskis, Tony D. James, Amit Nathubhai, Michael D. Threadgill, Timothy J. Woodman, Matthew D. Lloyd, Yoana D. Petrova |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug target Racemases and Epimerases Drug design Structure-activity relationships Biochemistry Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Drug Discovery Humans Potency Rational drug design Enzyme Inhibitors Molecular Biology Enzyme Assays Molecular Structure Chemistry Organic Chemistry Drug lipophilicity Enzyme inhibitors Stereoisomerism Isoenzymes 030104 developmental biology α-Methylacyl-CoA racemase (AMACR P504S) Drug Design 030220 oncology & carcinogenesis Lipophilicity Acyl Coenzyme A Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Jevglevskis, M, Lee, G L, Nathubhai, A, Petrova, Y, James, T, Threadgill, M, Woodman, T & Lloyd, M 2018, ' Structure-activity relationships of rationally designed AMACR 1A inhibitors ', Bioorganic and Medicinal Chemistry, vol. 79, pp. 145-154 . https://doi.org/10.1016/j.bioorg.2018.04.024 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2018.04.024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect