4.7 Article

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: An Emerging Strategy in Cancer Therapy

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 8, 页码 3840-3856

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01121

关键词

-

资金

  1. National Natural Science Foundation of China [81602948, 81773581, 81773639, 81803363]
  2. Natural Science Foundation of Jiangsu Province of China [BK20160746]
  3. China Postdoctoral Science Foundation [1600010006, 2018T110576]
  4. National Major Science and Technology Project of China (Innovation and Development of New Drugs) [2015ZX09101032, 2017ZX09302003]
  5. Priority Academic Program Development of Jiangsu Higher Education Institutions
  6. Program for Outstanding Scientific and Technological Innovation Team of Jiangsu Higher Education [YY20180315004]
  7. 111 Project [B16046]
  8. Double First-Class University Project [CPU2018GY02]

向作者/读者索取更多资源

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pleiotropic transcription factor, especially for its complex and dual effects in cancer. With the continuous growing research, new regulatory modes and new functions of Nrf2 and tumor-promoting effects of Nrf2 in malignant transformed tumors have become increasingly clear. Accumulating evidence has established that Nrf2 contributes to the whole process of pathogenesis, progression, metastasis, and prognosis of cancer, and Nrf2 could be a promising target in cancer therapy. However, the development of Nrf2 inhibitor is still limited. In this perspective, we will briefly describe the biological function and modulating network of Nrf2, stress its oncogenic role, and point out possible ways to inhibit Nrf2, as well as summarize the reported Nrf2 inhibitors.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

Review Pharmacology & Pharmacy

Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery

Lei Wang, Xiaoli Xu, Zhengyu Jiang, Qidong You

ACTA PHARMACEUTICA SINICA B (2020)

Review Chemistry, Medicinal

p62 as a therapeutic target for tumor

Mengmin Tao, Tian Liu, Qidong You, Zhengyu Jiang

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2020)

Article Biochemistry & Molecular Biology

An affinity prediction approach for the ligand of E3 ligase Cbl-b and an insight into substrate binding pattern

Lv-Bin Hu, Xiu-Qi Hu, Qiong Zhang, Qi-Dong You, Zheng-Yu Jiang

Summary: Protein-protein interactions are crucial for cellular processes, and studying them using peptide motifs and computational methods can provide valuable insights for the development of small molecule inhibitors. In this study, a new 6-mer motif with significantly enhanced affinity was discovered for Cbl-b and phosphorylated substrates, demonstrating the importance of structural optimization and activity enhancement mechanisms for PPI blockers.

BIOORGANIC & MEDICINAL CHEMISTRY (2021)

Review Chemistry, Medicinal

Inhibitors of BCL2A1/Bfl-1 protein: Potential stock in cancer therapy

Xue Li, Junwei Dou, Qidong You, Zhengyu Jiang

Summary: Bfl-1, an important anti-apoptotic protein, lacks developed inhibitors with ideal activity and selectivity, and its therapeutic potential is yet to be fully explored.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2021)

Review Biochemistry & Molecular Biology

Regulation of Nrf2 by phosphorylation: Consequences for biological function and therapeutic implications

Tian Liu, Yi-Fei Lv, Jing-Long Zhao, Qi-Dong You, Zheng-Yu Jiang

Summary: NRF2 is involved in antioxidant pathways and physiological processes, dysregulation is linked to diseases, phosphorylation by kinases is critical in regulating NRF2 activity. Various kinases positively or negatively regulate NRF2 activity through phosphorylation of different sites.

FREE RADICAL BIOLOGY AND MEDICINE (2021)

Article Chemistry, Medicinal

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability

Peng-Ju Zhu, Ze-Zhou Yu, Yi-Fei Lv, Jing-Long Zhao, Yuan-Yuan Tong, Qi-Dong You, Zheng-Yu Jiang

Summary: The study describes the rational design, synthesis, and structure-activity relationships of Mcl-1 inhibitors. The most potent compound 40 showed high affinity and superior selectivity for Mcl-1, activating the apoptosis signal pathway in an Mcl1-dependent manner.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Article Chemistry, Medicinal

Discovery of DDO-2213 as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia

Weilin Chen, Xin Chen, Dongdong Li, Jianrui Zhou, Zhengyu Jiang, Qidong You, Xiaoke Guo

Summary: The WDR5-MLL1 inhibitor compound 63 (DDO-2213) presented potent inhibitory effects and in vivo efficacy, showing potential for treating MLL-rearranged cancers.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

Editorial Material Chemistry, Medicinal

Proteolysis-targeting chimeras: a kaleidoscope of targeted protein degradation

Yi Mou, Shuai Wen, Xinxing Gao, Zheng-Yu Jiang

FUTURE MEDICINAL CHEMISTRY (2022)

Article Chemistry, Medicinal

ARE-PROTACs Enable Co-degradation of an Nrf2-MafG Heterodimer

Jianai Ji, Sinan Ma, Yuxuan Zhu, Jinglong Zhao, Yuanyuan Tong, Qidong You, Zhengyu Jiang

Summary: PROTAC technology is a potential strategy to degrade undruggable proteins. By constructing a new Nrf2 degrader called C2, the Nrf2-MafG heterodimer was selectively degraded, leading to the inhibition of Nrf2 transcriptional activity and improved sensitivity of NSCLC cells to ferroptosis and therapeutic drugs.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Article Chemistry, Medicinal

Development of Orally Bioavailable Amidobenzimidazole Analogues Targeting Stimulator of Interferon Gene (STING) Receptor

Zheng-Yu Jiang, Qi-Dong You, Xiao-Li Xu, Nan-Nan Chen, Han Zhang, Qiang-Sheng Zhu, Ting Zeng, Wei Dai, Ye-Ling Zhou, Guo-Feng Xin, Bei-Duo Wu, Si-Jia Gong

Summary: By modifying and optimizing the structure of mono-aminobenzimidazole (ABZI), nanomolar STING agonists were obtained. Compounds D59 and D61 significantly increased the transcription of IFN-beta and CXCL10, and induced phosphorylation of STING downstream proteins in THP1 cells. Furthermore, compound D61 exhibited favorable pharmacokinetic properties and effectively inhibited tumor growth in a mouse tumor model.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Article Chemistry, Multidisciplinary

Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation

Yuhui Jin, Jing Fan, Ruyan Wang, Xuanyu Wang, Ning Li, Qidong You, Zhengyu Jiang

Summary: Event-driven bifunctional molecules, such as PROTAC technology, have been successfully used to degrade proteins of interest (POI). In this study, we propose a versatile ligation to scavenging approach to terminate event-driven degradation. This approach utilizes a TCO-modified dendrimer and tetrazine-modified PROTACs to rapidly scavenge intra-cellular free PROTACs and halt the degradation of specific proteins in living cells. This work presents a flexible chemical knockdown approach for controlling the levels of POI in living cells.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2023)

Article Biochemistry & Molecular Biology

Novel Hydrogen Sulfide Hybrid Derivatives of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Alleviate Inflammation and Oxidative Stress in Acute Experimental Colitis

Xian Zhang, Keni Cui, Xiaolu Wang, Yuanyuan Tong, Chihong Liu, Yuechao Zhu, Qidong You, Zhengyu Jiang, Xiaoke Guo

Summary: Ulcerative colitis (UC) is an inflammatory disease with unknown cause that may be related to intestinal inflammation and oxidative stress. The molecular hybridization of two drug fragments represents a novel strategy for achieving a common pharmacological goal. This study synthesized a series of hybrid derivatives by combining an inhibitor of the Keap1-Nrf2 pathway with two established H2S-donor moieties, resulting in a drug candidate (DDO-1901) that showed a more potent therapeutic effect for UC treatment by improving defense against oxidative stress and reducing inflammation.

ANTIOXIDANTS (2023)

Article Chemistry, Medicinal

Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors

Ziquan Zhao, Ruitian Dong, Qidong You, Zhengyu Jiang

Summary: Oxidative stress is associated with various pathological conditions, and the transcription factor Nrf2 plays a crucial role in regulating cellular defense against oxidative and electrophilic damage. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 through non-electrophilic means has emerged as a promising approach to activate Nrf2. Recent advances in drug discovery have led to the development of small-molecule Keap1-Nrf2 PPI inhibitors with potent activity and favorable drug-like properties. This Perspective summarizes the latest progress in this field and discusses future prospects and challenges.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Review Chemistry, Medicinal

An updated patent review of Nrf2 activators (2020-present)

Ziquan Zhao, Ruitian Dong, Keni Cui, Qidong You, Zhengyu Jiang

Summary: The Nrf2 pathway plays a crucial role in protecting cells against oxidative stress, and activating this pathway has potential therapeutic implications for oxidative stress-related chronic diseases. This review summarizes the biological effects of Nrf2, the regulatory mechanism of the Keap1-Nrf2-ARE pathway, and the development of Nrf2 activators.

EXPERT OPINION ON THERAPEUTIC PATENTS (2023)

Article Biochemistry & Molecular Biology

Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification

Li Li, Nannan Chen, Dandan Xia, Shicheng Xu, Wei Dai, Yuanyuan Tong, Lei Wang, Zhengyu Jiang, Qidong You, Xiaoli Xu

Summary: The study identified DDO-6600 as a covalent modifier of Hsp90, which inhibits tumor cell proliferation, induces apoptosis, and reduces cell motility.

CELL CHEMICAL BIOLOGY (2021)

暂无数据