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
Department of Chemistry, Michigan State University 578 S. Shaw Ln. East Lansing Michigan 48824 USA
Department of Pharmacology and Toxicology, Michigan State University 1355 Bogue St. East Lansing Michigan 48824 USA
RSC Med Chem. 2022 Nov 16;14(1):74-84. doi: 10.1039/d2md00211f. eCollection 2023 Jan 25.
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.
NRF2是一种转录因子，可控制细胞对各种应激源的反应，如活性氧和氮物种。因此，它在抑制肿瘤发生中起关键作用，但癌细胞中NRF2的组成型表达会导致对化疗药物产生抗性并促进转移。因此，抑制NRF2途径是新药的一个靶点，特别是与卡铂和5-氟尿嘧啶等已有的化疗药物联合使用时。已经发现了一类新的NRF2抑制剂，如取代烟腈类化合物，如MSU38225。在这项工作中，研究了结构变化对NRF2抑制的影响。通过这些研究，我们鉴定出了一些活性与最初发现的化合物相当或更好，但溶解度大大提高的化合物。合成过程涉及多种金属催化反应，包括钛多组分偶联反应以及各种钯和铜偶联反应。除了抑制NRF2活性外，这些新化合物还抑制了NRF2途径被组成型激活的肺癌细胞的增殖和迁移。
