Abstract
WRN helicases play a key role in DNA replication, repair, and other processes in a variety of tumors. It has become one of the hot targets of genotoxic drugs, but the effect and mechanism of targeting WRN against prostate cancer is still unclear. In our previous study, we found a quinazoline compound kzl052, which has a WRN-dependent inhibitory effect on prostate cancer cells, but its molecular mechanism needs to be further explored. In this study, kzl052 significantly inhibited the growth of PC3 (IC(50) = 0.39 ± 0.01 μM) and LNCaP (IC(50) = 0.11 ± 0.01 μM) cells in vitro and showed a good inhibition effect on PCa in vivo. It inhibits PC3 cell growth by binding to WRN proteins and affecting its non-enzymatic function. Then the mechanism of kzl052 against prostate cancer progression was revealed to be by regulating the stability of DNA replication forks and the RB pathway. This study will provide a theoretical basis and treatment strategy for targeting WRN helicase in the treatment of prostate cancer.