Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA

PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-09, Vol.64 (17), p.12630-12650
Main Authors: Wang, Cheng, Qu, Lailiang, Li, Shang, Yin, Fucheng, Ji, Limei, Peng, Wan, Luo, Heng, Lu, Dehua, Liu, Xingchen, Chen, Xinye, Kong, Lingyi, Wang, Xiaobing
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Catalytic Domain
Cell Line, Tumor
Drug Design
Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein - chemistry
Enhancer of Zeste Homolog 2 Protein - metabolism
Female
Genes, BRCA1 - physiology
Humans
Molecular Structure
Poly(ADP-ribose) Polymerase Inhibitors - chemistry
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Protein Binding
Triple Negative Breast Neoplasms - drug therapy
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Summary:PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and EZH2 inhibitors, and the most promising compound, 5a, showed good inhibitory activity against PARP-1 and EZH2 and good inhibitory effects on MDA-MB-231 (IC50 = 2.63 μM) and MDA-MB-468 (IC50 = 0.41 μM) cells with wild-type BRCA. Compared with that of olaparib, the growth inhibitory activities against these two cell types increased by approximately 15- and 80-fold, respectively, which was even more effective than the combination of olaparib and tazemetostat/GSK126. 5a can induce autophagy death of tumor cells and cause less damage to normal cells. Therefore, 5a, as a first-in-class dual PARP and EZH2 inhibitor, is a potential anticancer drug candidate for the treatment of TNBC.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00567