Genomic mutation lies at the crux of cancer development, propagation, and relapse. Cancer-causing mutation often arises from exogenous sources such as sunlight and chemical exposure; yet, endogenous mutation can also actively contribute to cancer development. Considerable evidence implicates APOBEC3B (A3B), a host C-to-U DNA deaminase, as a major source of mutation in breast cancer.1 A3B is over-expressed in greater than 50% of primary breast cancers and 90% of breast cancer cell lines.1 Tumors that over-express A3B have twice as many overall mutations as low A3B expressing tumors.1 A3B knockdown studies directly link its activity to an increased frequency of genomic uracil content, C-to-T transitions, cell cycle deviations, and DNA fragmentation.1As part of our on-going effort to test the hypothesis that small molecule inhibition of A3B will decrease the overall mutation rate in breast cancer cells and ultimately slow tumor evolution, the Harki and Harris Labs have completed the high-throughput screening (HTS) of approximately 500,000 small molecules. Previous work from our laboratories has identified both covalent and non-covalent inhibitors of related deaminase APOBEC3G (A3G).2-4 This talk will highlight our ongoing efforts to develop first-in-class inhibitors of A3B through derivative synthesis of established A3G inhibitors as well as A3B-focused HTS.1Burns, M. B.; Lackey, L.; Carpenter, M. A.; Rathore, A.; Land, A. M.; Leonard, B.; Refsland, E. W.; Kotandeniya, D.; Tretyakova, N.; Nikas, J. B.; Yee, D.; Temiz, N. A.; Donohue, D. E.; McDougle, R. M.; Brown, W. L.; Law, E. K.; Harris, R. S. Nature 2013 , 494, 366.2Li, M.; Shandilya, S. M. D.; Carpenter, M. A.; Rathore, A.; Brown, W. L.; Perkins, A. L.; Harki, D. A.; Solberg, J.; Hook, D. J.; Pandey, K. K.; Parniak, M. A.; Johnson, J. R.; Krogan, N. J.; Somasundaran, M.; Ali, A.; Schiffer, C. A.; Harris, R. S. ACS Chem. Biol. 2012 , 7, 506.3Olson, M. E.; Li, M.; Harris, R. S.; Harki, D. A. ChemMedChem 2013 , 8, 112.  4Olson, M. E.; Abate-Pella, D.; Perkins, A. L.; Li, M.; Carpenter, M. A.; Rathore, A.; Harris, R. S.; Harki, D. A. Submitted.

Development of small molecule inhibitors of the breast cancer oncoprotein APOBEC3B

248th National Meeting (2014)

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