PDF(Pubmed)
Abstract：
Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of protein function. In an attempt to explore protein degradation by means of autophagy we combine arylidene-indolinones reported to bind the autophagy-related LC3B-protein and ligands of the PDEδ lipoprotein chaperone, the BRD2/3/4-bromodomain containing proteins and the BTK- and BLK kinases. Unexpectedly, the resulting bifunctional degraders do not induce protein degradation by means of macroautophagy, but instead direct their targets to the ubiquitin-proteasome system. Target and mechanism identification reveal that the arylidene-indolinones covalently bind DCAF11, a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define a drug-like DCAF11-ligand class that enables exploration of this E3 ligase in chemical biology and medicinal chemistry programs. The arylidene-indolinone scaffold frequently occurs in natural products which raises the question whether E3 ligand classes can be found more widely among natural products and related compounds.
摘要：
靶向蛋白酶体和自噬蛋白降解，经常采用双功能模式，是调节蛋白质功能的新范例。为了通过自噬探索蛋白质降解，我们结合了据报道与自噬相关的LC3B蛋白和PDEδ脂蛋白伴侣配体的亚芳基吲哚酮，含有BRD2/3/4-溴结构域的蛋白质和BTK-和BLK激酶。出乎意料的是,产生的双功能降解物不会通过巨自噬诱导蛋白质降解，而是将它们的目标指向泛素-蛋白酶体系统。靶标和机制鉴定表明，亚芳基吲哚酮共价结合了CUL4A/B-RBX1-DDB1-DCAF11E3连接酶中的底物受体DCAF11。回火的α，β-不饱和吲哚啉酮亲电试剂定义了类似药物的DCAF11配体类别，可以在化学生物学和药物化学程序中探索这种E3连接酶。亚芳基-吲哚啉酮支架经常发生在天然产物中，这提出了一个问题，即E3配体类别是否可以在天然产物和相关化合物中更广泛地发现。
