Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

Abstract

The cGAS-STING signaling plays an integral role in the host immune response, and the abnormal activation of cGAS-STING is highly related to various autoimmune diseases. Therefore, targeting the cGAS-STING-TBK1 axis has become a promising strategy in therapy of autoimmune diseases. Herein, we summarized the key pathways mediated by the cGAS-STING-TBK1 axis and various cGAS-STING-TBK1 related autoimmune diseases, as well as the recent development of cGAS, STING, or TBK1 selective inhibitors and their potential application in therapy of cGAS-STING-TBK1 related autoimmune diseases. Overall, the review highlights that inhibiting cGAS-STING-TBK1 signaling is an attractive strategy for autoimmune disease therapy.

cGAS–STING, an important signaling pathway in diseases and their therapy

“…Among other analogs, Compound 22, a C7-cyclohexyl analog, was demonstrated to inhibit IL-6 secretion in 3T3-L1 cells, although further studies revealed limitations in applying each of these compounds. [336][337][338][339] Other small molecule TBK1 inhibitors Idronoxil (IDX), a synthetic flavonoid closely related to daidzein, was recently demonstrated to effectively inhibit STING signaling. Specifically, IDX prevented the formation of the TBK1 and STING complex, blocking the phosphorylation of TBK1 at Ser172, and ultimately preventing the nucleosomal transcription of IRF3 and NF-κB.…”

STING antagonists, synthesized via Povarov–Doebner type multicomponent reaction

“…See reference for experimental details. 33 7-(3-Methyl-1H-pyrazol-4-yl)-8,9,10,11-tetrahydro-3Hpyrazolo[4,3-a]phenanthridine (18). See reference for experimental details.…”

“…16 With further mounting evidence suggesting implication of the cGAS-STING-TBK1 axis in various diseases where inflammation contributes towards disease onset, 17 the cGAS-STING-TBK1 pathway has been viewed as an attractive target towards the amelioration of associated symptoms correlated with these autoimmune disorders and spurred discovery of therapeutic moieties seeking to modulate the activities of cGAS, TBK1 or STING. [16][17][18] Solved crystal structures of human cGAS has since facilitated the recent identification of potent cGAS inhibitors such as compound S3 by Zhao et al 19 (IC 50 = 4.9 μM against human cGAS) and CU-76 by Padilla-Salinas and colleagues 20 (IC 50 = 0.27 μM against murine cGAS) through respective in silico virtual screening methodologies and subsequent optimization. Similarly, the selective targeting of TBK1 has been reported by both academic and pharma scientists.…”

STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases

“…The importance of the cGAS/STING pathway in the onset and progression of such myriad inflammatory and autoimmune diseases has recently sparked interest in the development of pharmacological agents to block STING pathway activation, including small molecule competitive and covalent inhibitors and proteolysis-targeting chimeras (PROTACs), , and plans have been announced to begin phase I clinical trials of a cGAS antagonist . Among the most promising agents reported to date are RU.521, a selective and potent cGAS inhibitor that occupies the active site of cGAS which decreases its affinity for ATP without affecting dsDNA binding, and H-151, a covalent STING inhibitor that blocks STING palmitoylation and subsequent interaction with TBK1, which is critical to STING signaling .…”