Bertrand Hélène C, Schaap Marjolein, Baird Liam, Georgakopoulos Nikolaos D, Fowkes Adrian, Thiollier Clarisse, Kachi Hiroko, Dinkova-Kostova Albena T, Wells Geoff
UCL School of Pharmacy, University College London , 29/39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee , Dundee, DD1 9SY, Scotland, United Kingdom.
J Med Chem. 2015 Sep 24;58(18):7186-94. doi: 10.1021/acs.jmedchem.5b00602.
The transcription factor Nrf2 regulates the expression of a large network of cytoprotective and metabolic enzymes and proteins. Compounds that directly and reversibly inhibit the interaction between Nrf2 and its main negative regulator Keap1 are potential pharmacological agents for a range of disease types including neurodegenerative conditions and cancer. We describe the development of a series of 1,4-diphenyl-1,2,3-triazole compounds that inhibit the Nrf2-Keap1 protein-protein interaction (PPI) in vitro and in live cells and up-regulate the expression of Nrf2-dependent gene products.
转录因子Nrf2调控着一大组具有细胞保护和代谢功能的酶及蛋白质的表达。能够直接且可逆地抑制Nrf2与其主要负调控因子Keap1之间相互作用的化合物，是包括神经退行性疾病和癌症在内的一系列疾病类型的潜在药物。我们描述了一系列1,4 - 二苯基 - 1,2,3 - 三唑化合物的研发情况，这些化合物在体外和活细胞中均能抑制Nrf2 - Keap1蛋白 - 蛋白相互作用（PPI），并上调Nrf2依赖的基因产物的表达。
