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

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 ( = 354 nM), we found the active compound which exhibited improved Nur77-binding capability ( = 91 nM) and excellent antiproliferative activiti...

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Published in:Journal of medicinal chemistry 2023-12, Vol.66 (23), p.15847-15866
Main Authors: Qin, Jingbo, Niu, Boning, Chen, Xiaohui, Hu, Cheng, Lu, Sheng, Li, Hongsheng, Liu, Weihao, Li, Jiayi, Teng, Zihao, Yang, Yinghuang, Hu, Hongyu, Xu, Yang, Huo, Shuaidong, Wu, Zhen, Qiu, Yingkun, Zhou, Hu, Fang, Meijuan
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Indoles - chemistry
Mice
Triple Negative Breast Neoplasms - pathology
Zebrafish
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Summary: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 ( = 354 nM), we found the active compound which exhibited improved Nur77-binding capability ( = 91 nM) and excellent antiproliferative activities against breast cancer cell lines. Interestingly, 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, Nur77-dependently caused mitochondria dysfunction and induced the caspase-dependent apoptosis by mediating the TP53 phosphorylation pathway. Moreover, significantly suppressed MDA-MB-231 xenograft tumor growth but had no apparent side effects in mice and zebrafish. Overall, demonstrated to be the first Nur77 modulator mediating the TP53 phosphorylation pathway that has the potential as a novel anticancer agent for TNBC.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c01336