Covalent Inhibitors of KEAP1 with Exquisite Selectivity

被引：0

作者：

Fejes, Imre ^{[1
]}

Markacz, Piroska ^{[1
]}

Tatai, Janos ^{[1
]}

Rudas, Monika ^{[1
]}

Dunkel, Petra ^{[1
]}

Gyuris, Mario ^{[1
]}

Nyerges, Miklos ^{[1
]}

Provost, Nicolas ^{[2
]}

Duvivier, Valerie ^{[2
]}

Delerive, Philippe ^{[2
]}

Martiny, Virginie ^{[2
]}

Bristiel, Alexandra ^{[2
]}

Vidal, Brice ^{[2
]}

Richardson, William ^{[3
]}

Rothweiler, Elisabeth M. ^{[3
]}

Tranberg-Jensen, Jeppe ^{[3
]}

Manning, Charlotte E. ^{[3
]}

Sweeney, Melissa N. ^{[3
]}

Chalk, Rod ^{[3
]}

Huber, Kilian V. M. ^{[3
]}

Bullock, Alex N. ^{[3
]}

Herner, Andras ^{[1
]}

Seedorf, Klaus ^{[2
]}

Vinson, Cedric ^{[2
]}

Weber, Csaba ^{[1
]}

Kotschy, Andras ^{[1
]}

机构：

[1] Servier Res Inst Med Chem, H-1031 Budapest, Hungary

[2] Inst Rech Servier, F-91190 Gif Sur Yvette, France

[3] Univ Oxford, Ctr Med Discovery, Nuffield Dept Med, Oxford OX3 7FZ, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 23期

关键词：

INTERFACE; PROVIDES; PATHWAY;

D O I：

10.1021/acs.jmedchem.4c02019

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：21208 / 21222

页数：15

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