Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
ACS Chem Biol. 2022 Sep 16;17(9):2404-2410. doi: 10.1021/acschembio.2c00439. Epub 2022 Aug 25.
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.
免疫调节酰亚胺类药物（IMiDs），如沙利度胺及其类似物，是用于开发蛋白水解靶向嵌合体（PROTAC）的最常用的 E3 连接酶配体之一。虽然 IMiDs 的典型新底物（即 Ikaros 和 Aiolos）通常被认为是 PROTAC 的非预期靶标，但保持这些新底物的降解也为用单一化合物协同降解多种蛋白质提供了机会。在这里，我们报告了 ALV-07-082-03 的开发，它是一种由 palbociclib（一种 FDA 批准的 CDK4/6 抑制剂）与 DKY709 偶联而成的 CDK4/6/Helios 三重降解剂，DKY709 是一种新型基于 IMiD 的 Helios 降解剂。CDK4/6 和 Helios 的药理学共降解导致癌细胞下游信号和增殖的强烈抑制，并增强了 IL-2 分泌的去抑制。因此，我们不仅证明了通过将替代分子胶作为 E3 连接酶配体纳入 PROTAC 来合理重新定向新底物特异性的可能性，而且我们的研究结果还表明，靶向 CDK4/6 和 Helios 可能具有协同作用。
