Guo Menglu, He Shipeng, Cheng Junfei, Li Yu, Dong Guoqiang, Sheng Chunquan
School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
ACS Med Chem Lett. 2022 Jan 12;13(2):298-303. doi: 10.1021/acsmedchemlett.1c00670. eCollection 2022 Feb 10.
The development of KRAS-PDEδ protein-protein interaction (PPI) inhibitors is generally hampered by limited antitumor activity. Herein, the first hydrophobic tagging (HyT)-based PDEδ degraders were designed. Compound efficiently bound to PDEδ and induced degradation of PDEδ in SW480 colon cancer cells. As compared with PDEδ inhibitor deltazinone, HyT-based degrader exhibited improved antitumor activity toward KRAS mutant cancer cells. This study highlighted the potential of HyT as a valuable chemical tool for tumorigenic PDEδ knockdown, which could be developed into a promising strategy for antitumor drug discovery.
KRAS-PDEδ蛋白-蛋白相互作用（PPI）抑制剂的开发通常因抗肿瘤活性有限而受阻。在此，设计了首个基于疏水标记（HyT）的PDEδ降解剂。化合物有效地结合PDEδ并诱导SW480结肠癌细胞中PDEδ的降解。与PDEδ抑制剂deltazinone相比，基于HyT的降解剂对KRAS突变癌细胞表现出更好的抗肿瘤活性。这项研究突出了HyT作为一种用于致瘤性PDEδ敲低的有价值化学工具的潜力，这可能发展成为一种有前景的抗肿瘤药物发现策略。
