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

Yoana D Petrova, Katty Wadda, Amit Nathubhai, Maksims Yevglevskis, Paul J Mitchell, Tony D James, Michael D Threadgill, Timothy J Woodman, Matthew D Lloyd*

*Corresponding author for this work

Research output: Contribution to JournalArticlepeer-review


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 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.

Original languageEnglish
Pages (from-to)103264
Number of pages6
JournalBioorganic Chemistry
Early online date7 Sept 2019
Publication statusPublished - 1 Nov 2019

Bibliographical note

Copyright © 2019 Elsevier Inc. All rights reserved.


  • Colorimetry
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors/chemical synthesis
  • High-Throughput Screening Assays
  • Humans
  • Molecular Structure
  • Pyrazoles/chemical synthesis
  • Pyrimidines/chemical synthesis
  • Quinolines/chemical synthesis
  • Racemases and Epimerases/antagonists & inhibitors
  • Small Molecule Libraries/chemical synthesis
  • Structure-Activity Relationship


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