2. Academic Validation
  3. Design, synthesis, and biological evaluation of N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as anticancer agents targeting Nur77-mediated endoplasmic reticulum stress

Design, synthesis, and biological evaluation of N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as anticancer agents targeting Nur77-mediated endoplasmic reticulum stress

  • Bioorg Chem. 2025 Feb:155:108113. doi: 10.1016/j.bioorg.2024.108113.
Hongyu Hu 1,  Fangfang Wen 2,  Tidong Zhen 3,  Minda Zhang 3,  Jingbo Qin 3,  Jiangang Huang 1,  Zhirong Chen 4,  Mingyue Yu 5,  Shengwei Hu 3,  Meijuan Fang 6,  Jin-Zhang Zeng 7
Affiliations

Affiliations

  • 1 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China; Community Health Service Center of Dashi Panyu, Guangzhou 511430, China.
  • 3 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 4 The Second People's Hospital of Panyu Guangzhou, Guangzhou 511430, China.
  • 5 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China; College of Chemsitry and Bioengineering, Yichun 336000, China.
  • 6 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: fangmj@xmu.edu.cn.
  • 7 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China. Electronic address: jzzeng@xmu.edu.cn.
PMID: 39787915 DOI: 10.1016/j.bioorg.2024.108113
Abstract

Targeting endoplasmic reticulum (ER) stress-induced Apoptosis has attracted considerable research interest in anti-cancer drug development. Nur77 is a potential therapeutic target in many cancers and several Nur77 modulators have recently been identified as effective Anticancer agents by activating ER stress. As an ongoing work, this study reports a new series of novel N1-(2-(adamantan-1-yl)-1H-indol-5-yl)-N2-(substituent)-1,2-dicarboxamides as potent Nur77 modulators that cause ER stress-induced Apoptosis. Among this new series, most compounds show improved cytotoxicity against liver Cancer (HepG2 and Huh7) and breast Cancer (MCF-7 and MDA-MB-231) cell lines. The representative analog 15h dramatically induces Nur77 expression and cell Apoptosis, showing excellent growth inhibition of HepG2 and MCF-7 cells (IC50 < 5.0 μM). Mechanistically, 15h binds (KD = 0.477 μM) and activates Nur77-mediated ER stress through the PERK-ATF4 and IRE1 signaling pathways, thereby inducing cell Apoptosis. In vivo, 15h treatment strongly suppresses HepG2 xenograft tumor growth (tumor shrink by 54.06 %). In summary, we synthesize a series of novel indole derivatives, among which 15h has significantly improved pharmacological activity against various Cancer cells. We further identify 15h as a novel ligand of Nur77, which may serve a therapeutic lead for developing new Cancer therapy.

Keywords

Anticancer activity; Apoptosis; Endoplasmic reticulum stress; Indole derivatives; Nur77; Target identification.

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