PDF(Pubmed)
Abstract：
Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.
摘要：
分子胶可以诱导靶蛋白和泛素连接酶之间的接近以诱导靶降解，但是发现它们的策略仍然有限。我们筛选了3,200个生物活性小分子，并确定C646需要neddylation依赖性蛋白质降解来诱导细胞毒性。尽管组蛋白乙酰转移酶p300是C646的典型靶标，但我们提供了大量证据表明C646直接靶向并降解Exportin-1（XPO1）。由C646诱导的多种细胞表型在表达已知XPO1C528S药物抗性等位基因的细胞中被消除。虽然XPO1催化许多货物蛋白的核到细胞质的运输，它也直接结合染色质。我们证明p300和XPO1共同占据数百个染色质基因座。使用C646或已知的XPO1调节剂S109降解XPO1会减少XPO1和p300的染色质占用，从而使XPO1能够直接靶向表型p300抑制。这项工作强调了耐药等位基因的实用性，并进一步验证了XPO1作为染色质状态的可靶向调节因子。
