Design,Synthesis,and Biological Evaluations Of Novel IDO/HDAC Dual Inhibitors

Tumor immunotherapy is one of the most important therapeutic methods after surgery,chemoradiotherapy and tumor targeting therapy.The combination of tumor immunotherapy and other treatment methods has become a hot research and development trend in the treatment of cancer.Indoleamine-2,3-dioxygenase（IDO）is important targets for tumor immunotherapy by acting on tumor microenvironment,improving tumor immunosuppression and enhancing immune signal transduction.Epigenetic modification is closely related to the occurrence and development of tumors,and histone deacetylase（HDAC）inhibitors show high anticancer activity in vitro and in vivo.Several studies have shown that epigenetic therapy can reverse tumor immune escape,promote the regulation of T cell apoptosis,and improve the body’s anti-tumor immune response by blocking cell proliferation.Therefore,epigenetic drugs and tumor immunotherapy have potential synergistic effects.We are committed to the design and synthesis of a new class of IDO/HDAC dual-target inhibitors,to further explore the mechanism of action of the compounds and the anti-cancer effect,in order to give full play to the advantages of tumor immunotherapy and epigenetic drugs.We screened the activity of some HDAC inhibitors which we synthesized previously at IDO1 enzyme level,and the results showed that compound QZ-2-26 had moderate inhibitory activity against IDO1(IC_50,IDO1=937.6 nM)and HDAC6(IC_50,HDAC6=5.2 nM).On the basis of QZ-2-26,we learned from the dominant structure and active functional group of IDO1 and HDAC6inhibitors,and designed four aspects of chemical modification respectively with different steric hindrance and electronic effect of substituents.According to activity screening results at the enzyme level,the isohydroxamic acid group was the necessary functional group to maintain the inhibitory activity against IDO/HDAC.Compound2c showed the best inhibitory activity of HDAC6 with the IC₅₀ of 1.1 nM,while compound 2d was the most active IDO1 inhibitor with the IC₅₀ of 5.9 nM.Compound1k showed very good inhibitory activity against IDO1 and HDAC6(IC_50,IDO1=76.0nM;IC_50,HDAC6=4.9 nM),which is superior to positive compounds INCB and SAHA.In HeLa cell-based IDO1 activity assay,1k was a non-competitive inhibitor with the IC₅₀ of 27.1 nM.Compound 1k showed excellent broad-spectrum anti-tumor activity in vitro anti-tumor cell proliferation experiments.To sum up,compound 1k is an excellent dual target inhibitor of IDO/HDAC,and its physiological activity and mechanism in vivo need to be further explored.