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.

中文翻译：

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选择性SWI / SNF功能的化学抑制剂与ATR抑制在癌细胞杀伤中协同作用。

SWI / SNF（BAF）复合物是由组合组装产生的一系列ATP依赖的染色质重塑剂的多样化家族，这些突变突变并认为可导致20％的人类癌症和大量神经系统疾病。BAF复合物的基因激活功能对于许多细胞类型的生存能力至关重要，从而限制了小分子抑制剂的发展。为了规避SWI / SNF抑制作用的潜在毒性，我们鉴定了抑制这些复合物特异性抑制功能但相对无毒且在杀灭癌细胞方面与ATR抑制剂具有重要协同作用的小分子。我们的研究为ATR / ATM抑制作用的治疗性提高提供了途径，并为化学合成杀伤BAF复合物的致死性作为癌症的治疗策略提供了证据。