Design, Synthesis, and Structure–Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition

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.