PROJECT 2 – CHEMICAL MODULATION OF DNA DEAMINASES IN CANCER

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

PROJECT 2 – CHEMICAL BIOLOGY OF DNA DEAMINASES IN CANCER ABSTRACT APOBEC3 enzymes are single-stranded DNA cytosine-to-uracil deaminases that normally protect cells from viral infections. However, APOBEC3A (A3A) and APOBEC3B (A3B) have been implicated in causing cancer mutations that drive tumor evolution and contribute to the development of drug resistance and, ultimately, therapy failure. Our Program’s overarching and unifying hypothesis is that A3A and/or A3B inhibition will prevent a large proportion of new mutations, thereby improving the durability of current treatments and resulting in better overall outcomes. To address this hypothesis our Program is focused on understanding the structural biology of DNA deaminases in cancer (Project 1); characterizing the biology of DNA deaminases in cancer (Project 3); and developing chemical inhibitors and degraders of A3A and A3B deaminases (here). These highly integrated projects are supported by service cores for administration (Core A), proteins and assays (Core B), and computational chemistry, biophysics, and bioinformatics (Core C). Project 2 – Chemical Biology of DNA Deaminases in Cancer will be the center of chemical innovation for the Program by, in Aim 1, exploiting our expertise in nucleic acid-A3 molecular recognition to develop nucleic acid-based inhibitors of A3A and A3B deaminase activity and nucleic acid-based chemical degraders of A3A and A3B. In Aim 2, we will use A3A- and A3B-binding small molecules, already identified from high-throughput screening, computational designs, fragment-based inhibitor testing, mass spectrometry-based assays, and rationally designed peptidomimetics to develop potent, cell-permeable, and non-cytotoxic A3A and A3B ligands. Lead compounds from these series will be optimized by collaborative Program activities and further developed into A3A/B inhibitors and degraders. Taken together, Project 2 will provide new insights into the chemical biology of APOBEC enzymes and contribute to the achievement of our overall research objectives including our long-term goal of blocking the evolution of A3-positive cancer cells.