Fejes Imre, Markacz Piroska, Tatai Janos, Rudas Monika, Dunkel Petra, Gyuris Mario, Nyerges Miklos, Provost Nicolas, Duvivier Valérie, Delerive Philippe, Martiny Virginie, Bristiel Alexandra, Vidal Brice, Richardson William, Rothweiler Elisabeth M, Tranberg-Jensen Jeppe, Manning Charlotte E, Sweeney Melissa N, Chalk Rod, Huber Kilian V M, Bullock Alex N, Herner Andras, Seedorf Klaus, Vinson Cedric, Weber Csaba, Kotschy Andras
Servier Research Institute of Medicinal Chemistry, Zahony u. 7., H-1031 Budapest, Hungary.
Institute de Recherche Servier, 22 Route 128, 91190 Gif-sur-Yvette, France.
J Med Chem. 2024 Dec 12;67(23):21208-21222. doi: 10.1021/acs.jmedchem.4c02019. Epub 2024 Nov 21.
The NRF2-KEAP1 interaction is central for cytoprotection against stresses, giving it high clinical significance. Covalent modification of KEAP1 is an efficient approach, but the covalent inhibitors used in the clinic carry undesired side effects originating in their moderate selectivity. Starting with a phenotypic screen, we identified a new covalent inhibitor chemotype that was optimized to deliver a series of potent and highly selective KEAP1 binders. While the developed compounds showed both cellular and in vivo activity, upregulating antioxidant response element-dependent target genes, they showed no genotoxicity in vitro. The lead compound exhibited broad selectivity in activity-based protein profiling and showed no significant interaction with a panel of commonly studied receptors nor with a broad panel of kinases. The nature of its interaction with KEAP1 and the origin of its selectivity were revealed by X-ray crystallography.
NRF2-KEAP1相互作用对于细胞抵御应激至关重要，具有很高的临床意义。KEAP1的共价修饰是一种有效的方法，但临床使用的共价抑制剂因其选择性一般而具有不良副作用。从表型筛选开始，我们鉴定出一种新的共价抑制剂化学类型，并对其进行优化以获得一系列强效且高选择性的KEAP1结合剂。虽然所开发的化合物显示出细胞活性和体内活性，上调了抗氧化反应元件依赖性靶基因，但它们在体外没有遗传毒性。先导化合物在基于活性的蛋白质谱分析中表现出广泛的选择性，并且与一组常用研究的受体以及一组广泛的激酶均无明显相互作用。通过X射线晶体学揭示了其与KEAP1相互作用的性质及其选择性的来源。
