2. Academic Validation
  3. Discovery of 5-(Pyrimidin-2-ylamino)-1 H-indole-2-carboxamide Derivatives as Nur77 Modulators with Selective and Potent Activity Against Triple-Negative Breast Cancer

Discovery of 5-(Pyrimidin-2-ylamino)-1 H-indole-2-carboxamide Derivatives as Nur77 Modulators with Selective and Potent Activity Against Triple-Negative Breast Cancer

  • J Med Chem. 2023 Nov 20. doi: 10.1021/acs.jmedchem.3c01336.
Jingbo Qin 1 2,  Boning Niu 1 3,  Xiaohui Chen 1 4,  Cheng Hu 1,  Sheng Lu 1,  Hongsheng Li 1,  Weihao Liu 1,  Jiayi Li 1,  Zihao Teng 1,  Yinghuang Yang 1,  Hongyu Hu 5,  Yang Xu 1,  Shuaidong Huo 1,  Zhen Wu 1,  Yingkun Qiu 1,  Hu Zhou 1,  Meijuan Fang 1
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
  • 2 Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
  • 3 Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
  • 5 Xingzhi College, Zhejiang Normal University, Lanxi 321004, China.
PMID: 37983615 DOI: 10.1021/acs.jmedchem.3c01336
Abstract

The orphan nuclear receptor Nur77 has been validated as a potential drug target for treating breast Cancer. Therefore, focusing on the SAR study of the lead 8b (KDSPR(Nur77) = 354 nM), we found the active compound ja which exhibited improved Nur77-binding capability (KDSPR(Nur77) = 91 nM) and excellent antiproliferative activities against breast Cancer cell lines. Interestingly, ja acted as a potent and selective Nur77 antagonist, displaying good potency against triple-negative breast Cancer (TNBC) cell lines but did not inhibit human normal breast Cancer cell line MCF-10A (SI > 20). Exceptionally, ja Nur77-dependently caused mitochondria dysfunction and induced the caspase-dependent Apoptosis by mediating the TP53 phosphorylation pathway. Moreover, ja significantly suppressed MDA-MB-231 xenograft tumor growth but had no apparent side effects in mice and zebrafish. Overall, ja demonstrated to be the first Nur77 modulator mediating the TP53 phosphorylation pathway that has the potential as a novel Anticancer agent for TNBC.

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