APOBEC3 (A3) enzymes are a family of DNA cytosine-to-uracil deaminases that participate in a variety of cellular functions. APOBEC3G (A3G) targets the cDNA replication intermediate of HIV-1, which ultimately results in G-to-A hypermutations in the viral genome.1 Enhancements to the genetic diversity of HIV-1 contribute to the adaptability of the virus and its ability to develop drug resistance. A related deaminase, APOBEC3B (A3B), has been found to be highly upregulated in human breast cancer specimens, suggesting that A3B is an endogenous source of mutation in breast cancer.2 Elevated A3B levels in breast cancer cells may contribute to tumor evolution, and likely, the development of drug resistance. Given the importance of A3 enzymes in human disease, small molecule A3 inhibitors may yield valuable probe compounds, as well as potential therapeutics.High-throughput screening (HTS) and chemical optimization of hit molecules have resulted in the discovery of two chemotypes of A3G inhibitors.3, 4 Our molecules covalently target a solvent-accessible cysteine on A3G that is located adjacent to the enzyme active site and facilitate a loss of enzyme activity. More recently, we have identified a family of non-covalent inhibitors of A3 enzymes based on a decomposed HTS hit that we characterized.5 Curiously, the parent, unstable chemotype is present in >130 samples in the NIH MLPCN collection.This presentation will introduce the A3-family of DNA cytosine deaminases as novel targets for the development of therapies to treat HIV-1 and cancer. Our recently discovered, first-in-class A3G covalent inhibitors will be presented,3, 4 as well as next-generation compounds that modulate enzyme activity by a non-covalent mechanism of action.51. Albin, J. S.; Harris, R. S. Expert Rev. Mol. Med. 2010  , 12, e4.2. Burns, M. B.; et al. Nature 2013  , 494, 366-370.3. Li, M.; et al. ACS Chem. Biol. 2012  , 7, 506-517.4. Olson, M. E.; et al. ChemMedChem 2013  , 8, 112-117.5. Olson, M.E.; et al. Submitted.

Development of small molecule inhibitors of APOBEC3 DNA cytosine deaminases

247th National Meeting (2014)

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