posted on 2021-08-29, 12:33authored byCheng Wang, Lailiang Qu, Shang Li, Fucheng Yin, Limei Ji, Wan Peng, Heng Luo, Dehua Lu, Xingchen Liu, Xinye Chen, Lingyi Kong, Xiaobing Wang
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.