Structure-Activity Relationship Study of 1H-Pyrrole-3-carbonitrile Derivatives as STING Receptor Agonists.

Abstract

The use of small agonists to target stimulators of interferon genes (STING) has been demonstrated to be a promising strategy for the treatment of various cancers and infectious diseases. Herein, we discovered a series of 1H-pyrrole-3-carbonitrile derivatives as potential STING agonists. On this basis, the structure-activity relationship of this scaffold was studied by introducing various substituents on the aniline ring system. Representative compounds 7F, 7P, and 7R all displayed comparable activities to the reported STING agonist SR-717 in binding various hSTING alleles and induced reporter signal in human THP1 cell lines. Model compound 7F induced phosphorylation of TBK1, IRF3, p65, and STAT3 in a STING-dependent fashion and stimulated the expression of target genes IFNB1, CXCL10, and IL6 in a time-dependent manner in human THP1 cells. Our findings afforded a series of novel STING agonists with promising potential.