KRAS-PDEδ protein–protein interaction represents an appealing target for cancer therapy. However, fast release of high-affinity inhibitors from PDEδ hampered drug binding affinity and antiproliferative activity. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules targeting PDEδ were designed. By employment of PDEδ inhibitor deltazinone (2) and cereblon ligand pomalidomide (6), a series of potent PROTAC PDEδ degraders were obtained. The most promising compound 17f efficiently induced PDEδ degradation and demonstrated significantly improved antiproliferative potency in KRAS mutant SW480 cells. Compound 17f also achieved significant tumor growth inhibition in the SW480 colorectal cancer xenograft model. This proof-of-concept study provided a new strategy to validate the druggability of KRAS-PDEδ interaction and offered an effective lead compound for the treatment of KRAS mutant cancer.

中文翻译：

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发现用于治疗KRAS突变性大肠癌的新型PDEδ降解剂。

KRAS-PDEδ蛋白与蛋白的相互作用代表了癌症治疗的诱人靶标。但是，从PDEδ快速释放高亲和力抑制剂会阻碍药物结合亲和力和抗增殖活性。为了克服这些限制，设计了第一个靶向PDEδ的靶向蛋白水解的嵌合小分子（PROTAC）。通过使用PDEδ抑制剂deltazinone（2）和cereblon配体pomalidomide（6），获得了一系列有效的PROTACPDEδ降解剂。最有前途的化合物17f在KRAS突变体SW480细胞中有效诱导PDEδ降解并显示出显着提高的抗增殖能力。化合物17f在SW480大肠癌异种移植模型中，也获得了显着的肿瘤生长抑制。这项概念验证研究为验证KRAS-PDEδ相互作用的可药物性提供了新的策略，并为治疗KRAS突变型癌症提供了有效的先导化合物。