Targeting STING in senescence with small-molecule inhibitors
Andrea Ablasser
Global Health Institute, Swiss Federal Institute of Technology, Lausanne, CH-1015 Lausanne
Senescence, a cellular program triggered by various distinct stresses, has emerged as an important contributor to aging-associated diseases. One critical feature, which underlies some of the maladaptive effects of senescent cells, is their inflammatory secretome, collectively referred to as the senescence-associated secretory phenotype (SASP). Recently, we have defined a critical role for the innate DNA sensing pathway comprising cyclic GMP-AMP synthase (cGAS) and Stimulator of interferon genes (STING) in the regulation of the SASP. Briefly, we found that cGAS recognizes aberrant cytosolic chromatin fragments (CCFs) in senescent cells and, in turn, triggers the production of SASP factors through STING. Our finding of aberrant activation of innate immune signalling in senescence raises the possiblity that targeting this pathway may provide beneficial effects in senescence-associated pathologies. However, the development of pharmacological inhibitors that specifically act on molecules of the innate DNA sensing pathway has remained a major challenge. In this talk, we report the discovery of highly potent and selective small molecule antagonists of stimulator of interferon genes (STING). In depth characterisation of the compounds uncovered an entirely unexpected mechanism to pharmacologically antagonise STING signalling. We show that the discovered compounds reduce STING-mediated inflammatory cytokine production in various contexts in vitro and, moreover, we demonstrate their therapeutic utility in autoinflammatory disease in mice. Finally, we discuss the effect of acute inhibition of STING in contexts of cellular senescence. In sum, our work describes the first ever reported STING antagonists and provide a proof-of-concept of the realization of anti-STING therapies. We propose targeting STING with small molecules may be benefical for diseases caused by chronic inflammation, potentially also diseases driven by the SASP.
Global Health Institute, Swiss Federal Institute of Technology, Lausanne, CH-1015 Lausanne
Senescence, a cellular program triggered by various distinct stresses, has emerged as an important contributor to aging-associated diseases. One critical feature, which underlies some of the maladaptive effects of senescent cells, is their inflammatory secretome, collectively referred to as the senescence-associated secretory phenotype (SASP). Recently, we have defined a critical role for the innate DNA sensing pathway comprising cyclic GMP-AMP synthase (cGAS) and Stimulator of interferon genes (STING) in the regulation of the SASP. Briefly, we found that cGAS recognizes aberrant cytosolic chromatin fragments (CCFs) in senescent cells and, in turn, triggers the production of SASP factors through STING. Our finding of aberrant activation of innate immune signalling in senescence raises the possiblity that targeting this pathway may provide beneficial effects in senescence-associated pathologies. However, the development of pharmacological inhibitors that specifically act on molecules of the innate DNA sensing pathway has remained a major challenge. In this talk, we report the discovery of highly potent and selective small molecule antagonists of stimulator of interferon genes (STING). In depth characterisation of the compounds uncovered an entirely unexpected mechanism to pharmacologically antagonise STING signalling. We show that the discovered compounds reduce STING-mediated inflammatory cytokine production in various contexts in vitro and, moreover, we demonstrate their therapeutic utility in autoinflammatory disease in mice. Finally, we discuss the effect of acute inhibition of STING in contexts of cellular senescence. In sum, our work describes the first ever reported STING antagonists and provide a proof-of-concept of the realization of anti-STING therapies. We propose targeting STING with small molecules may be benefical for diseases caused by chronic inflammation, potentially also diseases driven by the SASP.
