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

Abstract

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 (IC 50 = 2.63 μM) and MDA-MB-468 (IC 50 = 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.

Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects

“…Therefore, Wang et al designed a series of dual inhibitors of PARP1 and EZH2 (Figure ). These researchers replaced the benzylmorpholine structure of tazemetostat with a linker and combined it with the pharmacophore of olaparib. , Structure–activity relationship (SAR) studies showed that the introduction of methyl ( 17b ) at the ortho position of the amide enhanced the activity, and the activity of compounds with an electron-withdrawing group ( 17c ) on the benzene ring was lower than that of compounds with an electron-donating group ( 17d ). The replacement of the amino group on the benzene ring by an amide structure yielded 17e .…”

Dual targeting, a new strategy for novel PARP inhibitor discovery

“…In the work reported by Wang, et al, they used compound 1 and tazemetostat as the starting point to design the dual PARP and EZH2 inhibitors (73). Analysis of the complex of tazemetostat-EZH2 revealed that the benzylmorpholine moiety oriented to the solvent and can tolerate structural modification.…”

Discovery of 4-Hydroxyquinazoline Derivatives as Small Molecular BET/PARP1 Inhibitors That Induce Defective Homologous Recombination and Lead to Synthetic Lethality for Triple-Negative Breast Cancer Therapy

“…Some BRD4 or PARP-related dual-targeted inhibitors have been shown to have good effects on malignant cancers, including pancreatic cancer and breast cancer. − Based on our previous findings, simultaneous inhibition of BRD4 and PARP1 by ADTL-BPI1901 ( 11 ) significantly triggered the death of cancer cells . Nonetheless, further development of dual-targeted inhibitors is necessary due to the relatively weak activity of ADTL-BPI1901 on PARP1 and its unsatisfactory bioavailability.…”