Human cells can express up to 9 single-stranded DNA cytosine-to-uracil (C-to-U) deaminases. One family member, APOBEC3G (A3G), deaminates cDNA replication intermediates of retroviruses such as HIV-1, and these lesions lead to genomic strand G-to-A mutations.1 This process contributes to viral genetic diversity, which allows escape from immune responses and the development of resistance to drug therapies. A different family member, APOBEC3B (A3B), was recently implicated as the major source of G-to-A mutation in breast cancer.2 This enzyme may therefore contribute to tumor development, and possibly, to immune escape and anticancer drug resistance.Given the prominent role of APOBEC3-family enzymes in these human diseases, we have initiated a campaign to discover first-in-class small molecule inhibitors. Utilizing high-throughput screening and chemical synthesis, we have discovered two unique chemical scaffolds that inhibit A3G by covalently engaging (A3G) Cys321, which is located proximal to the enzyme active site.3, 4 More recent efforts have revealed an entirely new chemotype of A3G inhibitor that likely functions through a non-covalent mechanism of inhibition. Chemical derivatization of this lead molecule has yielded compounds that inhibit related enzyme, A3B, with low micromolar activity. Our progress towards developing both A3G and A3B inhibitors will be presented.Selected References:1.   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.

Small molecule inhibition of APOBEC3-mediated DNA cytosine deamination

246th National Meeting (2013)

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