cGAS PROTAC TH35 is an effective, selective CRBN-recruiting cGAS-targeting PROTAC degrader with DC50 of 0.9 uM and 4.6 uM in THP-1 and RAW 264.7 cells respectively, Dmax >90% at 20 uM.
TH35 inhibits dsDNA-induced cGAS activation in both THP1-Lucia ISG and RAW-Lucia ISG cells, with IC50 values of 1.8 and 4.8 uM respectively.
TH35 efficiently induces degradation of both human cGAS (h-cGAS) and murine cGAS (m-cGAS).
TH35 effectively induces cGAS degradation mediated by the ubiquitin–proteasome pathway in a CRBN-dependent manner.
TH35 specifically targets cGAS to inhibit the expression of interferon regulatory factor (IRF)-inducible genes rather than acting on downstream proteins of the cGAS-STING pathway.
TH35 dose-dependently inhibits the phosphorylation of STING, TBK1 and IRF3 in both THP-1 and RAW 264.7 cells.
TH35 suppresses the mRNA expression of IFNB in response to dsDNA, including 45-bp immune stimulatory DNA (ISD), herpes simplex virus-1 (HSV-1), and HT-DNA, in THP-1 cells.
TH35 (20 and 50 mg/kg, i.p.) ameliorates DSS-induced colitis in mouse model of DSS-induced ulcerative colitis (UC), alleviates cGAS-mediated inflammation responses in vivo.