2. Academic Validation
  3. Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer

  • J Med Chem. 2024 Aug 8;67(15):13089-13105. doi: 10.1021/acs.jmedchem.4c01070.
Lie-Feng Ma 1,  Li Li Xu 2,  Ling-Jie Yuan 1,  Xi Yang 1,  Rui Wu 3,  Shu-Min Bao 1,  Yi-Li Chen 1,  Hong-Liang Duan 4,  Luo Fang 5,  Hua-Jun Zhao 2,  Zha-Jun Zhan 1
Affiliations

Affiliations

  • 1 Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China.
  • 2 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, P. R. China.
  • 3 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, P. R. China.
  • 4 Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, P. R. China.
  • 5 Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310014, P. R. China.
PMID: 39044437 DOI: 10.1021/acs.jmedchem.4c01070
Abstract

Triple-negative breast Cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced Apoptosis and Ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Keywords

NO donor; anti-metastasis; aurovertin; ferroptosis; triple negative breast cancer.

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