Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing
| Autor: | Chiung-Ying Chang, Gerald R. Crabtree, Sai Gourisankar, Vincent D. D’Andrea, Emily C. Dykhuizen, Emma J. Chory, Jacob G. Kirkland |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell type Synthetic lethality Ataxia Telangiectasia Mutated Proteins 01 natural sciences Biochemistry Article 03 medical and health sciences Neoplasms medicine Humans Protein Kinase Inhibitors 010405 organic chemistry Chemistry Cell Cycle Cancer General Medicine medicine.disease Chromatin Assembly and Disassembly HCT116 Cells Small molecule SWI/SNF 0104 chemical sciences Chromatin Cell biology 030104 developmental biology Cancer cell Molecular Medicine biological phenomena cell phenomena and immunity Function (biology) Transcription Factors |
| Zdroj: | ACS Chem Biol |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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