Open AccessChemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing
Author(s) -
Emma J. Chory,
Jacob G. Kirkland,
ChenMing Chang,
Vincent D'Andrea,
Sai Gourisankar,
Emily C. Dykhuizen,
Gerald R. Crabtree
Publication year - 2020
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.0c00312
Subject(s) - small molecule , cancer cell , synthetic lethality , biology , cancer , cancer research , function (biology) , swi/snf , gene , chemistry , microbiology and biotechnology , biochemistry , chromatin , genetics , chromatin remodeling , dna repair
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 nontoxic 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.