Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors
Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors
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DOI：
10.1021/acsmedchemlett.9b00631
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发表时间：
2020-04-09
影响因子：
4.2
通讯作者：
Moore, Terry W.
中科院分区：
文献类型：
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作者：
Lazzara, Phillip R.;Jain, Atul D.;Moore, Terry W.
由KEAP 1和NRF 2的蛋白质-蛋白质相互作用门控的氧化应激反应在过去十年中引起了人们的极大兴趣。该途径中的失调与疾病状态如多发性硬化症、类风湿性关节炎和糖尿病慢性伤口有关。许多已知的NRF 2活化剂在性质上是亲电的，并且可以通过几种生物学途径而不是仅仅通过氧化应激反应的活化来操作。最近，我们的实验室报道了一种非亲电的，单酸的，基于萘的NRF 2激活剂，在体外表现出良好的效力。在此，我们报告了基于萘的NRF 2激活剂的详细结构-活性关系，我们的单酸KEAP 1抑制剂的X-射线晶体结构，以及KEAP 1的NRF 2结合口袋的未充分探索区域的鉴定。
The oxidative stress response, gated by the protein-protein interaction of KEAP1 and NRF2, has garnered significant interest in the past decade. Misregulation in this pathway has been implicated in disease states such as multiple sclerosis, rheumatoid arthritis, and diabetic chronic wounds. Many of the known activators of NRF2 are electrophilic in nature and may operate through several biological pathways rather than solely through the activation of the oxidative stress response. Recently, our lab has reported a nonelectrophilic, monoacidic, naphthalene-based NRF2 activator which exhibited good potency in vitro. Herein, we report a detailed structure-activity relationship of naphthalene-based NRF2 activators, an X-ray crystal structure of our monoacidic KEAP1 inhibitor, and identification of an underexplored area of the NRF2 binding pocket of KEAP1.