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bioRxiv · 10.1101/660456

Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing

Chory, E. J.·Kirkland, J. G.·Chang, C.-y.·D'Andrea, V.·Gourisankar, S.·Dykhuizen, E. J.·Crabtree, G. J.
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Abstract

SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively non-toxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer.

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Chory, E. J., Kirkland, J. G., Chang, C.-y., D'Andrea, V., Gourisankar, S., Dykhuizen, E. J., Crabtree, G. J.. 2019-06-04. Inhibition of a Selective SWI/SNF Function Synergizes with ATR Inhibitors in Cancer Cell Killing. https://doi.org/10.1101/660456

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