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Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.

Publication ,  Journal Article
Chory, EJ; Kirkland, JG; Chang, C-Y; D'Andrea, VD; Gourisankar, S; Dykhuizen, EC; Crabtree, GR
Published in: ACS chemical biology
June 2020

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.

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Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

June 2020

Volume

15

Issue

6

Start / End Page

1685 / 1696

Related Subject Headings

  • Transcription Factors
  • Protein Kinase Inhibitors
  • Organic Chemistry
  • Neoplasms
  • Humans
  • HCT116 Cells
  • Chromatin Assembly and Disassembly
  • Cell Cycle
  • Ataxia Telangiectasia Mutated Proteins
  • 34 Chemical sciences
 

Citation

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Chory, E. J., Kirkland, J. G., Chang, C.-Y., D’Andrea, V. D., Gourisankar, S., Dykhuizen, E. C., & Crabtree, G. R. (2020). Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing. ACS Chemical Biology, 15(6), 1685–1696. https://doi.org/10.1021/acschembio.0c00312
Chory, Emma J., Jacob G. Kirkland, Chiung-Ying Chang, Vincent D. D’Andrea, Sai Gourisankar, Emily C. Dykhuizen, and Gerald R. Crabtree. “Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.ACS Chemical Biology 15, no. 6 (June 2020): 1685–96. https://doi.org/10.1021/acschembio.0c00312.
Chory EJ, Kirkland JG, Chang C-Y, D’Andrea VD, Gourisankar S, Dykhuizen EC, et al. Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing. ACS chemical biology. 2020 Jun;15(6):1685–96.
Chory, Emma J., et al. “Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.ACS Chemical Biology, vol. 15, no. 6, June 2020, pp. 1685–96. Epmc, doi:10.1021/acschembio.0c00312.
Chory EJ, Kirkland JG, Chang C-Y, D’Andrea VD, Gourisankar S, Dykhuizen EC, Crabtree GR. Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing. ACS chemical biology. 2020 Jun;15(6):1685–1696.
Journal cover image

Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

June 2020

Volume

15

Issue

6

Start / End Page

1685 / 1696

Related Subject Headings

  • Transcription Factors
  • Protein Kinase Inhibitors
  • Organic Chemistry
  • Neoplasms
  • Humans
  • HCT116 Cells
  • Chromatin Assembly and Disassembly
  • Cell Cycle
  • Ataxia Telangiectasia Mutated Proteins
  • 34 Chemical sciences