Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery
Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery
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DOI：
10.1021/acs.jmedchem.6b00228
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发表时间：
2016-04-28
影响因子：
7.3
通讯作者：
Kerns, Jeffrey K.
中科院分区：
文献类型：
--
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
Keap1是NRF2介导的细胞保护反应的关键调节因子，越来越多地被认为是氧化应激相关疾病的靶标。药物干预主要集中在通过Keap1半胱氨酸残基的共价修饰来减少NRF2泛素化的分子，但这种亲电化合物缺乏选择性，可能与靶外毒性有关。我们在这里报告了第一次使用基于片段的方法来直接靶向Keap1 Kelch-NRF2相互作用。X射线结晶学筛选在Keap1的NRF2结合口袋内发现了三个不同的片段结合热点，允许弱片段与Keap1具有纳摩尔亲和力的分子结合，同时保持药物样特性。这项工作导致了一种有前景的先导化合物，它与Keap1表现出紧密和选择性的结合，并在细胞和体内模型中激活NRF2的抗氧化反应，从而提供了一个高质量的化学探针来探索破坏Keap1-NRF2相互作用的治疗潜力。
KEAP1 is the key regulator of the NRF2-mediated cytoprotective response, and increasingly recognized as a target for diseases involving oxidative stress. Pharmacological intervention has focused on molecules that decrease NRF2-ubiquitination through covalent modification of KEAP1 cysteine residues, but such electrophilic compounds lack selectivity and may be associated with off-target toxicity. We report here the first use of a fragment-based approach to directly target the KEAP1 Kelch-NRF2 interaction. X-ray crystallographic screening identified three distinct hot-spots for fragment binding within the NRF2 binding pocket of KEAP1, allowing progression of a weak fragment hit to molecules with nanomolar affinity for KEAP1 while maintaining drug-like properties. This work resulted in a promising lead compound which exhibits tight and selective binding to KEAP1, and activates the NRF2 antioxidant response in cellular and in vivo models, thereby providing a high quality chemical probe to explore the therapeutic potential of disrupting the KEAP1-NRF2 interaction.