Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships.

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ID: 77177
2019
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Abstract
α-Methylacyl-CoA racemase (AMACR; P504S; EC 5.1.99.4) catalyses epimerization of 2-methylacyl-CoAs and is important for the degradation of branched-chain fatty acids and the pharmacological activation of ibuprofen and related drugs. It is also a novel drug target for prostate and other cancers. However, development of AMACR as a drug target has been hampered by the difficulties in assaying enzyme activity. Consequently, reported inhibitors have been rationally designed acyl-CoA esters, which are delivered as their carboxylate prodrugs. The novel colorimetric assay for AMACR based on the elimination of 2,4-dinitrophenolate was developed for high-throughput screening and 20,387 'drug-like compounds' were screened, with a throughput of 768 compounds assayed per day. Pyrazoloquinolines and pyrazolopyrimidines were identified as novel scaffolds and investigated as AMACR inhibitors. The most potent inhibitors have IC values of ~2 µM. The pyrazoloquinoline inhibitor 10a displayed uncompetitive inhibition, whilst 10j displayed mixed competitive inhibition. The pyrazolopyrimidine inhibitor 11k displayed uncompetitive inhibition. This is the first report of the identification of specific drug-like small-molecule AMACR inhibitors by high-throughput screening. Pyrazoloquinolines and pyrazolopyrimidines may also be useful as inhibitors of other CoA-utilizing enzymes.
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petrova2019identificationbioorganic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Petrova, Yoana D;Wadda, Katty;Nathubhai, Amit;Yevglevskis, Maksims;Mitchell, Paul J;James, Tony D;Threadgill, Michael D;Woodman, Timothy J;Lloyd, Matthew D;
Journal Bioorganic chemistry
Year 2019
DOI
S0045-2068(19)30398-0
URL
Keywords
prostate cancer structure-activity relationships high-throughput screening branched-chain fatty acids ibuprofen metabolism mixed competitive inhibition uncompetitive inhibition α-methylacyl-coa racemase (amacr p504s)

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