Design, Synthesis,
and Structure–Activity Relationship
of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating
the Relationship between Antitumor Immunity and HDACs Inhibition
posted on 2024-03-08, 13:33authored byJi-Long Duan, Chen-Chen Wang, Yinghui Yuan, Zi Hui, Hang Zhang, Nian-Dong Mao, Pengpeng Zhang, Bowen Sun, Jing Lin, Zishuo Zhang, Yuan Gao, Tian Xie, Xiang-Yang Ye
Histone deacetylases (HDACs) inhibitors such as vorinostat
(SAHA)
has been used to treat hematologic malignancies (rather than solid
tumors) and have been found to suppress the JAK/STAT, a critical signal
pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could
activate the type I interferons (IFN-I) pathway, facilitating downstream
effects such as STAT1 phosphorylation and immune activation. To elucidate
whether simultaneous inhibition of these two targets could interfere
with these two signal pathways, a series of pyridazinone-based PARP7/HDACs
dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor
for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating
the relationship between anticancer immunity and HDAC inhibition.