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

Petrova, Yoana, D., Wadda, Katty, Nathubhai, Amit, Yevglevskis, Maksims, Mitchell, Paul, J., James, Tony, D., Threadgill, Michael, D., Woodman, Timothy, J. and Lloyd, Matthew, D. (2019) Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure activity relationships. Bioorganic Chemistry, 92 (103264). pp. 1-6. ISSN 0045-2068

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α-Methylacyl-CoA racemase (AMACR; P504S; EC 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 highthroughput 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 IC50 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.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
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Depositing User: Amit Nathubhai
Date Deposited: 19 Sep 2019 10:08
Last Modified: 30 Sep 2020 10:47
ORCID for Amit Nathubhai: ORCID iD

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