Article
Discovery of Novel Small-Molecule Inhibitors of NF-κB Signaling with Antiinflammatory and Anticancer PropertiesClick to copy article linkArticle link copied!
- Lei ZhangLei ZhangDepartment of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80309, United StatesMore by Lei Zhang
- Lei ShiLei ShiDepartment of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80309, United StatesJiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. ChinaMore by Lei Shi
- Shafer Myers SoarsShafer Myers SoarsDepartment of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80309, United StatesMore by Shafer Myers Soars
- Joshua KampsJoshua KampsDepartment of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80309, United StatesMore by Joshua Kamps
- Hang Yin*Hang Yin*E-mail: [email protected]Department of Chemistry and Biochemistry and the BioFrontiers Institute, University of Colorado, Boulder, Colorado 80309, United StatesMore by Hang Yin
Abstract
Click to copy section linkSection link copied!
Excessive NF-κB activation contributes to the pathogenesis of numerous diseases. Small-molecule inhibitors of NF-κB signaling have significant therapeutic potential especially in treating inflammatory diseases and cancers. In this study, we performed a cell-based high-throughput screening to discover novel agents capable of inhibiting NF-κB signaling. On the basis of two hit scaffolds from the screening, we synthesized 69 derivatives to optimize the potency for inhibition of NF-κB activation, leading to successful discovery of the most potent compound Z9j with over 170-fold enhancement of inhibitory activity. Preliminary mechanistic studies revealed that Z9j inhibited NF-κB signaling via suppression of Src/Syk, PI3K/Akt, and IKK/IκB pathways. This novel compound also demonstrated antiinflammatory and anticancer activities, warranting its further development as a potential multifunctional agent to treat inflammatory diseases and cancers.
Copyright © 2018 American Chemical Society
Cited By
Click to copy section linkSection link copied!
This article is cited by 22 publications.
- Meng Wang, Guimei Li, Guiyang Jiang, Jinyuan Cai, Zhikun Liu, Rizhen Huang, Xiaochao Huang, Hengshan Wang. Novel NF-κB Inhibitor-Conjugated Pt(IV) Prodrug to Enable Cancer Therapy through ROS/ER Stress and Mitochondrial Dysfunction and Overcome Multidrug Resistance. Journal of Medicinal Chemistry 2024, 67
(8)
, 6218-6237. https://doi.org/10.1021/acs.jmedchem.3c02182
- Manpreet Bariana, Beilu Zhang, Jingyu Sun, Weiwei Wang, Jinping Wang, Elena Cassella, Faith Myint, Shaina A. Anuncio, Samedy Ouk, Hsiou-Chi Liou, Ming Tan, Hongjun Wang, Johannes L. Zakrzewski. Targeted Lymphoma Therapy Using a Gold Nanoframework-Based Drug Delivery System. ACS Applied Materials & Interfaces 2023, 15
(5)
, 6312-6325. https://doi.org/10.1021/acsami.2c17214
- Mei-Lin Tang, Haidong Li, Jin-Feng Ning, Xiaoyan Shen, Xun Sun. Discovery of First-in-Class TAK1–MKK3 Protein–Protein Interaction (PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitis through Modulating TNF-α Production. Journal of Medicinal Chemistry 2022, 65
(9)
, 6690-6709. https://doi.org/10.1021/acs.jmedchem.1c02198
- Stefano Federico, Luca Pozzetti, Alessandro Papa, Gabriele Carullo, Sandra Gemma, Stefania Butini, Giuseppe Campiani, Nicola Relitti. Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists. Journal of Medicinal Chemistry 2020, 63
(22)
, 13466-13513. https://doi.org/10.1021/acs.jmedchem.0c01049
- Guimei Li, Meng Wang, Li Luo, Demin Tang, Nan Xu, Rizhen Huang, Yong Yang, Guiping Chen, Zhikun Liu, Hengshan Wang, Xiaochao Huang. Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance. European Journal of Medicinal Chemistry 2025, 285 , 117249. https://doi.org/10.1016/j.ejmech.2025.117249
- Wei-Bin Yan, Wen-Xuan Li, Yue Zhang, Lu Yu, Yu-Lun Li, Yong-Jun Liu, Gui-Ge Hou, Qing-Guo Meng, Li-Ying Ma, Zi-Kai Geng. Treatment of rheumatoid arthritis with dissymmetric fluorine and pyridyl-substituted 3,5-bis(aryl)-4-piperidone derivatives by inhibition of NF-κB and MAPK activation. Arabian Journal of Chemistry 2024, 17
(2)
, 105528. https://doi.org/10.1016/j.arabjc.2023.105528
- Meng Wang, Guimei Li, Guiyang Jiang, Jingyuan Cai, Wentian Zhong, Rizhen Huang, Zhikun Liu, Xiaochao Huang, Hengshan Wang. Dual-targeting tumor cells hybrids derived from Pt(IV) species and NF-κB inhibitors enables cancer therapy through mitochondrial dysfunction and ER stress and overcomes cisplatin resistance. European Journal of Medicinal Chemistry 2024, 266 , 116095. https://doi.org/10.1016/j.ejmech.2023.116095
- Junli Huang, Zeli Ma, Zichao Yang, Zengzhu He, Jingna Bao, Xiaopeng Peng, Yao Liu, Ting Chen, Shumin Cai, Jianjun Chen, Zhenhua Zeng. Discovery of Ibrutinib-based BTK PROTACs with in vivo anti-inflammatory efficacy by inhibiting NF-κB activation. European Journal of Medicinal Chemistry 2023, 259 , 115664. https://doi.org/10.1016/j.ejmech.2023.115664
- Ming-Zhu Luan, Xiao-Fan Zhang, Yang Yang, Qing-Guo Meng, Gui-Ge Hou. Anti-inflammatory activity of fluorine-substituted benzo[h]quinazoline-2-amine derivatives as NF-κB inhibitors. Bioorganic Chemistry 2023, 132 , 106360. https://doi.org/10.1016/j.bioorg.2023.106360
- Ling Li, Sijie Yuan, Lin Lin, Fang Yang, Ting Liu, Chenglong Xu, Huiting Zhao, Jingxuan Chen, Peihua Kuang, Ting Chen, Wenzhen Liao, Jianjun Chen. Discovery of novel 2-aryl-4-bis-amide imidazoles (ABAI) as anti-inflammatory agents for the treatment of inflammatory bowel diseases (IBD). Bioorganic Chemistry 2022, 120 , 105619. https://doi.org/10.1016/j.bioorg.2022.105619
- Jia-Jia Sun, Xiao-Fan Zhang, Qing-Guo Meng, Hong-Juan Li, Chun-Hua Wang. Crystal structure and anti-inflammatory activity of (
E
)-7-fluoro-2-((5-methoxypyridin-3-yl)methylene)-3,4-dihydronaphthalen-1(2
H
)-one, C
17
H
14
FNO
2. Zeitschrift für Kristallographie - New Crystal Structures 2021, 236
(5)
, 1097-1099. https://doi.org/10.1515/ncrs-2021-0234
- Seongrak Sim, Sumi Lee, Seungyun Ko, Bich Phuong Bui, Phuong Linh Nguyen, Jungsook Cho, Kiho Lee, Jong-Soon Kang, Jae-Kyung Jung, Heesoon Lee. Design, synthesis, and biological evaluation of potent 1,2,3,4-tetrahydroisoquinoline derivatives as anticancer agents targeting NF-κB signaling pathway. Bioorganic & Medicinal Chemistry 2021, 46 , 116371. https://doi.org/10.1016/j.bmc.2021.116371
- Wei Cong, Yue Sun, Yi-Fan Sun, Wei-Bin Yan, Yu-Long Zhang, Zhong-Fei Gao, Chun-Hua Wang, Gui-Ge Hou, Jia-Jing Zhang. Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-кB activation. Journal of Enzyme Inhibition and Medicinal Chemistry 2021, 36
(1)
, 1621-1630. https://doi.org/10.1080/14756366.2021.1953996
- Thierno Moussa Seck, Fatou Dieng Faye, Aissatou Alioune Gaye, Ibrahima Elhadji Thiam, Ousmane Diouf, Mohamed Gaye, Pascal Retailleau. Synthesis of mono and bis-substituted asymmetrical compounds, (1-(pyridin-2-yl)ethylidene)carbonohydrazide and 1-(2'-hydroxybenzylidene)-5-(1'-pyridylethylidene)carbonohydrazone: Structural characterization and antioxidant activity study. European Journal of Chemistry 2020, 11
(4)
, 285-290. https://doi.org/10.5155/eurjchem.11.4.285-290.2023
- Yue Sun, Zhong-Fei Gao, Wei-Bin Yan, Bin-Rong Yao, Wen-Yu Xin, Chun-Hua Wang, Qing-Guo Meng, Gui-Ge Hou. Discovery of novel NF-кB inhibitor based on scaffold hopping: 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine. European Journal of Medicinal Chemistry 2020, 198 , 112366. https://doi.org/10.1016/j.ejmech.2020.112366
- Wei-Bin Yan, Yong-Jun Liu, Gui-Ge Hou, Wei Cong, Qing-Guo Meng. Crystal structure and anti-inflammatory activity of (3
E
,5
E
)-3,5-bis(4-fluorobenzylidene)-1-((4-fluorophenyl)sulfonyl)piperidin-4-one-dichloromethane (1/1), C
26
H
20
Cl
2
F
3
NO
3
S. Zeitschrift für Kristallographie - New Crystal Structures 2020, 235
(4)
, 947-949. https://doi.org/10.1515/ncrs-2020-0116
- Andrew Chen, Angela N. Koehler. Transcription Factor Inhibition: Lessons Learned and Emerging Targets. Trends in Molecular Medicine 2020, 26
(5)
, 508-518. https://doi.org/10.1016/j.molmed.2020.01.004
- Martin Krátký, Zsuzsa Baranyai, Šárka Štěpánková, Katarína Svrčková, Markéta Švarcová, Jiřina Stolaříková, Lilla Horváth, Szilvia Bősze, Jarmila Vinšová. N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and Their Analogues: Synthesis and Multitarget Biological Activity. Molecules 2020, 25
(10)
, 2268. https://doi.org/10.3390/molecules25102268
- An-Qi Wang, Ru-Ning Gao, Qing-Hao Luan, Ze-Ping Wang, Xiao-Ming Li, Gui-Ge Hou. Crystal structure and anti-inflammatory activity of (3
E
,5
E
)-3-(2-fluorobenzylidene)-1-((4-acetamidophenyl)sulfonyl)-5-(pyridin-3-ylmethylene)piperidin-4-one-methanol-hydrate (2/1/1), C
53
H
50
F
2
N
6
O
10
S
2. Zeitschrift für Kristallographie - New Crystal Structures 2020, 235
(2)
, 381-384. https://doi.org/10.1515/ncrs-2019-0686
- Yan-Qiu Zhou, Gui-Ge Hou, Qing-Guo Meng, Yun Hou. Crystal structure and anti-inflammatory activity of (3
E
,5
E
)-1-((4-chlorophenyl)sulfonyl)-3-(pyridin-4-ylmethylene)-5-(2-(trifluoromethyl)benzylidene)piperidin-4-one, C
25
H
18
ClF
3
N
2
O
3
S. Zeitschrift für Kristallographie - New Crystal Structures 2020, 235
(2)
, 411-413. https://doi.org/10.1515/ncrs-2019-0716
- Mariko Watanabe, Akihiro Sugawara, Yoshihiko Noguchi, Tomoyasu Hirose, Satoshi Ōmura, Toshiaki Sunazuka, Ryouichi Horie. Jietacins, azoxy natural products, as novel NF-κB inhibitors: Discovery, synthesis, biological activity, and mode of action. European Journal of Medicinal Chemistry 2019, 178 , 636-647. https://doi.org/10.1016/j.ejmech.2019.05.079
- Chang-Ming Su, Gui-Ge Hou, Chun-Hua Wang, Hong-Qin Zhang, Cheng Yang, Mei Liu, Yun Hou. Potential multifunctional agents with anti-hepatoma and anti-inflammation properties by inhibiting NF-кB activation. Journal of Enzyme Inhibition and Medicinal Chemistry 2019, 34
(1)
, 1287-1297. https://doi.org/10.1080/14756366.2019.1635124
Learn about these metrics
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.