Boosting the Discovery of Small Molecule Inhibitors of Glucose-6-Phosphate Dehydrogenase for the Treatment of Cancer, Infectious Diseases, and Inflammation.

We present an overview of small molecule glucose-6-phosphate dehydrogenase (G6PD) inhibitors that have potential for use in the treatment of cancer, infectious diseases, and inflammation. Both steroidal and nonsteroidal inhibitors have been identified with steroidal inhibitors lacking target selectivity. The main scaffolds encountered in nonsteroidal inhibitors are quinazolinones and benzothiazinones/benzothiazepinones. Three molecules show promise for development as antiparasitic (25 and 29) and anti-inflammatory (32) agents. Regarding modality of inhibition (MOI), steroidal inhibitors have been shown to be uncompetitive and reversible. Nonsteroidal small molecules have exhibited all types of MOI. Strategies to boost the discovery of small molecule G6PD inhibitors include exploration of structure-activity relationships (SARs) for established inhibitors, employment of high-throughput screening (HTS), and fragment-based drug discovery (FBDD) for the identification of new hits. We discuss the challenges and gaps associated with drug discovery efforts of G6PD inhibitors from in silico, in vitro, and in cellulo to in vivo studies.

• Publication year

  2022

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2022-03-03

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1021/acs.jmedchem.1c01577PMID 35239352PMCID PMC9553131
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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