Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, United States.
J Med Chem. 2023 May 11;66(9):6184-6192. doi: 10.1021/acs.jmedchem.2c02037. Epub 2023 Apr 25.
Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor traditionally thought of as a cellular protector. However, in many cancers, Nrf2 is constitutively activated and correlated with therapeutic resistance. Nrf2 heterodimerizes with small musculoaponeurotic fibrosarcoma Maf (sMAF) transcription factors, allowing binding to the antioxidant responsive element (ARE) and induction of transcription of Nrf2 target genes. While transcription factors are historically challenging to target, stapled peptides have shown great promise for inhibiting these protein-protein interactions. Herein, we describe the first direct cell-permeable inhibitor of Nrf2/sMAF heterodimerization. N1S is a stapled peptide designed based on AlphaFold predictions of the interactions between Nrf2 and sMAF MafG. A cell-based reporter assay combined with biophysical assays demonstrates that N1S directly inhibits Nrf2/MafG heterodimerization. N1S treatment decreases the transcription of Nrf2-dependent genes and sensitizes Nrf2-dependent cancer cells to cisplatin. Overall, N1S is a promising lead for the sensitization of Nrf2-addicted cancers.
核因子红细胞 2 相关因子 2 (Nrf2) 是一种转录因子，传统上被认为是一种细胞保护因子。然而，在许多癌症中，Nrf2 持续激活，并与治疗耐药性相关。Nrf2 与小肌肉腱膜纤维肉瘤 Maf（sMAF）转录因子形成异二聚体，允许与抗氧化反应元件（ARE）结合，并诱导 Nrf2 靶基因的转录。虽然转录因子在历史上难以作为靶点，但订书肽在抑制这些蛋白-蛋白相互作用方面显示出巨大的潜力。本文描述了第一个直接可渗透细胞的 Nrf2/sMAF 异二聚体抑制剂。N1S 是一种基于 Nrf2 和 sMAF MafG 之间相互作用的 AlphaFold 预测设计的订书肽。基于细胞的报告基因测定与生物物理测定相结合，证明 N1S 可直接抑制 Nrf2/MafG 异二聚体的形成。N1S 处理可降低 Nrf2 依赖性基因的转录，并使 Nrf2 依赖性癌细胞对顺铂敏感。总的来说，N1S 是一种很有前途的 Nrf2 成瘾性癌症增敏剂。
