Protein degradation technology based on hybrid small molecules is an emerging drug modality that has significant potential in drug discovery and as a unique method of post-translational protein knockdown in the field of chemical biology. Here, we report the first example of a novel and potent protein degradation inducer that binds to an allosteric site of the oncogenic BCR-ABL protein. BCR-ABL allosteric ligands were incorporated into the SNIPER (Specific and Nongenetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers) platform, and a series of in vitro biological assays of binding affinity, target protein modulation, signal transduction, and growth inhibition were carried out. One of the designed compounds, 6 (SNIPER(ABL)-062), showed desirable binding affinities against ABL1, cIAP1/2, and XIAP and consequently caused potent BCR-ABL degradation.

中文翻译：

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靶向癌蛋白BCR-ABL的变构位点作为有效靶蛋白降解的替代策略

基于杂化小分子的蛋白质降解技术是一种新兴的药物形式，在药物发现中具有巨大潜力，并且是化学生物学领域翻译后蛋白质敲除的独特方法。在这里，我们报告的新型和有效的蛋白质降解诱导剂的第一个例子，该诱导剂与致癌BCR-ABL蛋白的变构位点结合。BCR-ABL变构配体被整合到SNIPER（凋亡蛋白[IAP]依赖性蛋白的特定和非遗传抑制剂）平台中，并进行了一系列结合亲和力，靶蛋白调节，信号转导和生长抑制的体外生物学测定进行了。一种设计的化合物，6 （SNIPER（ABL）-062）对ABL1，cIAP1 / 2和XIAP表现出理想的结合亲和力，因此导致有效的BCR-ABL降解。