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

Abstract

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 7 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.

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment

“…This hypothesis forms the basis for the project we report here. In our ongoing PARP7-related dual inhibitor program, we have observed that the trifluoromethyl pyrimidine side chain could be replaced with a much larger attachment without losing PARP7 activity . We reason that an appropriate linker could be used in this region to attach a PD-L1 small-molecule inhibitor scaffold so that a novel class of bifunctional conjugate targeting PD-L1/PARP7 could be obtained.…”

Advances in Integrated Multi-omics Analysis for Drug-Target Identification

“…These drug targets encompass a range of biomolecules, including proteins, enzymes, cell-membrane receptors, DNA or RNA sequences, and key regulatory factors within cellular signaling pathways or biological processes [ 1 ].The accurate determination of drug targets enables the purposeful design of a series of drugs that have superior therapeutic effects, safety, and applicability. These drugs typically act more precisely on specific parts or mechanisms, thereby demonstrating remarkable curative effects and bringing significant breakthroughs in disease treatment [ 2 , 3 , 4 , 5 ]. In the early stages of drug development, target identification primarily relies on biochemical and molecular biology methods, but these methods are often inefficient and time-consuming.…”