Ji Jianai, Ma Sinan, Zhu Yuxuan, Zhao Jinglong, Tong Yuanyuan, You Qidong, Jiang Zhengyu
Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
J Med Chem. 2023 May 11;66(9):6070-6081. doi: 10.1021/acs.jmedchem.2c01909. Epub 2023 Mar 9.
Proteolysis-targeting chimera (PROTAC) technology has emerged as a potential strategy to degrade "undruggable" proteins in recent years. Nrf2, an aberrantly activated transcription factor in cancer, is generally considered undruggable as lacking active sites or allosteric pockets. Here, we constructed the chimeric molecule , which consists of an Nrf2-binding element and a CRBN ligand, as a first-in-class Nrf2 degrader. Surprisingly, was found to selectively degrade an Nrf2-MafG heterodimer simultaneously via the ubiquitin-proteasome system. impeded Nrf2-ARE transcriptional activity significantly and improved the sensitivity of NSCLC cells to ferroptosis and therapeutic drugs. The degradation character of ARE-PROTACs suggests that the PROTAC hijacking the transcription element of TFs could achieve co-degradation of the transcription complex.
近年来，蛋白酶靶向嵌合体（PROTAC）技术已成为一种降解“不可成药”蛋白的潜在策略。Nrf2是癌症中一种异常激活的转录因子，由于缺乏活性位点或变构口袋，通常被认为是不可成药的。在此，我们构建了一种嵌合分子，其由一个Nrf2结合元件和一个CRBN配体组成，作为首个Nrf2降解剂。令人惊讶的是，发现该嵌合分子可通过泛素-蛋白酶体系统同时选择性降解Nrf2-MafG异二聚体。该嵌合分子显著阻碍了Nrf2-ARE转录活性，并提高了非小细胞肺癌（NSCLC）细胞对铁死亡和治疗药物的敏感性。ARE-PROTACs的降解特性表明，劫持转录因子转录元件的PROTAC可实现转录复合物的共降解。
