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

Yoana Petrova, Katty Wadda, Amit Nathubhai, Maksims Jevglevskis, Paul Mitchell, Tony James, Michael Threadgill, Tim Woodman, Matthew Lloyd

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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 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 50 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.

Original languageEnglish
Article number103264
JournalBioorganic Chemistry
Early online date7 Sept 2019
Publication statusPublished - 1 Nov 2019


  • Branched-chain fatty acids
  • High-throughput screening
  • Ibuprofen metabolism
  • Mixed competitive inhibition
  • Prostate cancer
  • Structure-activity relationships
  • Uncompetitive inhibition
  • α-Methylacyl-CoA racemase (AMACR P504S)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry


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