(1035-D) Free cysteine profiling confirmed STING target engagement and identified potential covalent off-targets for a novel STING inhibitor
Tuesday, February 6, 2024
2:00 PM – 3:00 PM EST
Location: Exhibit Halls AB
Abstract: STING (stimulators of interferon genes) is an emerging innate immunity target which simultaneously stimulates inflammasome, senescence, Type 1 IFN and IL-6/TNFa inflammatory cytokines in response to DNA-based pathogenic disease triggers. Development of a novel potent STING inhibitor with a compelling biological profile in vitro and in vivo has provided a first-in-class opportunity to target this key self-DNA-sensing pathway to treat auto-immune diseases. In vivo, the STING inhibitor shows high clearance and formation of an active metabolite. The combination of short PK and covalent nature of the compound makes it crucial to have target engagement measurements to fully understand the TE/PD relationship. To elucidate compound Mode of Action (MoA) and to measure cellular on- and off-target reactivity, we deployed cutting-edge technology where team developed a robust and stringent cysteine covalent profiling pipeline and showed STING target engagement and site of interaction of the compound in cells. Notably, this was the first example of using discovery proteomics to show covalent cell target engagement and selectivity.