小脑
泛素连接酶
帕博西利布
药物发现
化学
生物
细胞生物学
生物化学
癌症
泛素
遗传学
基因
乳腺癌
转移性乳腺癌
作者
Alyssa Verano,Inchul You,Katherine A. Donovan,Nada Mageed,Hong Yue,Radosław P. Nowak,Eric S. Fischer,Eric S. Wang,Nathanael S. Gray
标识
DOI:10.1021/acschembio.2c00439
摘要
Immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogues, are some of the most commonly utilized E3 ligase ligands for the development of proteolysis targeting chimeras (PROTACs). While the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are often considered to be unwanted targets of PROTACs, maintaining the degradation of these neo-substrates also provides the opportunity to synergistically degrade multiple proteins with a single compound. Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios triple degrader that consists of palbociclib, an FDA-approved CDK4/6 inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader. Pharmacological codegradation of CDK4/6 and Helios resulted in potent suppression of downstream signaling and proliferation in cancer cells, as well as enhanced derepression of IL-2 secretion. Thus, not only do we demonstrate the possibility of rationally redirecting the neo-substrate specificity of PROTACs by incorporating alternative molecular glue molecules as E3 ligase ligands but our findings also suggest that cotargeting CDK4/6 and Helios may have synergistic effects.
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