选择性SWI/SNF功能的化学抑制剂与ATR抑制协同作用以杀死癌细胞。
Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.
作者信息
Chory Emma J, Kirkland Jacob G, Chang Chiung-Ying, D'Andrea Vincent D, Gourisankar Sai, Dykhuizen Emily C, Crabtree Gerald R
机构信息
Department of Chemical Engineering, Stanford University, Stanford, California 94305, United States.
Departments of Developmental Biology and Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.
出版信息
ACS Chem Biol. 2020 Jun 19;15(6):1685-1696. doi: 10.1021/acschembio.0c00312. Epub 2020 May 27.
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 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.
摘要
SWI/SNF（BAF）复合物是一类多样的ATP依赖型染色质重塑因子家族，由组合装配产生，在20%的人类癌症和大量神经疾病中发生突变，并被认为与这些疾病有关。BAF复合物的基因激活功能对许多细胞类型的生存能力至关重要，这限制了小分子抑制剂的开发。为了规避SWI/SNF抑制的潜在毒性，我们鉴定出了一些小分子，它们能抑制这些复合物的特定抑制功能，但相对无毒，并且重要的是，它们能与ATR抑制剂协同作用来杀死癌细胞。我们的研究为增强ATR/ATM抑制的治疗提供了一条途径，并为BAF复合物的化学合成致死性作为癌症治疗策略提供了证据。
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