Exploring structural effects in a new class of NRF2 inhibitors
Exploring structural effects in a new class of NRF2 inhibitors
复制标题
探索新型 NRF2 抑制剂的结构效应
DOI：
10.1039/d2md00211f
复制
发表时间：
2023
影响因子：
4.1
通讯作者：
Odom, Aaron L.
中科院分区：
文献类型：
--
作者：
Hou, Zhilin;Lockwood, Lizbeth;Zhang, Di;Occhiuto, Christopher J.;Mo, Linqing;Aldrich, Kelly E.;Stoub, Hayden E.;Gallo, Kathleen A.;Liby, Karen T.;Odom, Aaron L.
NRF 2是一种转录因子，控制细胞对各种应激源的反应，如活性氧和氮物质。因此，它在抑制癌发生中起关键作用，但癌细胞中的组成型NRF 2表达导致对化疗药物的抗性并促进转移。因此，抑制NRF 2途径是新药的目标，特别是与已建立的化疗药物如卡铂和5-氟尿嘧啶联合使用。已经发现了一类新的NRF 2抑制剂，其具有取代的烟腈，例如MSU 38225。在这项工作中，研究了结构变化对NRF 2抑制的影响。通过这些研究，我们鉴定了一些化合物，其活性与初始命中一样好或更好，但溶解度大大提高。合成涉及多种金属催化反应，包括钛多组分偶联反应和各种Pd和Cu偶联反应。除了抑制NRF 2活性外，这些新化合物还抑制了肺癌细胞的增殖和迁移，其中NRF 2途径被组成性激活。
NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. A new class of NRF2 inhibitors has been discovered with substituted nicotinonitriles, such as MSU38225. In this work, the effects on NRF2 inhibition with structural changes were explored. Through these studies, we identified a few compounds with as good or better activity than the initial hit but with greatly improved solubility. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated.