Table 3 The inhibitors targeting the cGAS-STING pathway

cGAS Inhibitors

A151

Competes with DNA

Inhibits IFN-I production; attenuates brain inflammatory burden

[235, 236]

Suramin

Displaces dsDNA from cGAS

Reduces IFN-I production

[237]

AMDs (Hydroxychloroquine,

Quinacrine,

Chloroquine)

Disrupts the binding of dsDNA with cGAS

Reduces IFN-β production

[238, 239]

X6

Disrupts the binding of dsDNA with cGAS

Reduces ISG expression and cGAMP production

[239]

XQ2B

Targets the interface between cGAS and dsDNA and phase separation

Suppresses the elevated levels of type I interferon and proinflammatory cytokines

[240]

CU.32, CU.76

Binds to the zinc-binding site of cGAS

Reduces IFN-β production

[241]

4-sulfonic calix [6] arene

Influences both the dsDNA-binding site on cGAS and the 2′,3′-cGAMP

Dose-dependent inhibition in poly dA:dT-induced IFN-β release

[242]

RU.521

Occupies the catalytic site of cGAS; reduce its affinity for ATP and GTP

Suppresses IFN- I production

[243]

PF-06928215

Has high affinity for the catalytic site

Exhibits no inhibitory potency against dsDNA-induced IFN-β expression in cellular cGAS assays

[244]

G140, G150

Inhibits the catalytic activity

Inhibits dsDNA-triggered interferon expression

[245]

Compound S3

Inhibits the catalytic activity

-

[246]

Compound 25

Occupies the catalytic site of cGAS

Dramatically suppresses the dsDNA-induced phosphorylation of the downstream STING/TBK1/IRF3 signaling and the mRNA expression of the downstream ISGs

[247, 248]

EGCG

Disrupts cGAS activation by inhibiting of G3BP1

Inhibits self DNA-induced autoinflammatory responses and ISG expression

[249]

aspirin

Inhibits cGAS by enforcing its acetylation

Suppresses self-DNA-induced autoimmunity in AGS patient cells and in an AGS mouse model

[194]

FTO

Decreases cGAS mRNA stability by inhibition of m6A modification

Significantly alleviated brain injury and microglia-mediated inflammatory response

[250]

Leptomycin B

Blocks the nuclear export of cGAS

Inhibits the expression of IFN-β and ISG mRNA

[251]

Entinostat (MS275)

Suppresses cGAS transcription by inhibiting HDAC3

Reduces IFN-β production

[109]

Trichostatin A (TSA)

Suppresses cGAS transcription by inhibiting HDAC3

Reduces IFN-β production

[109]

Activin A

Inhibits cGAS-STING-mediated autophagy by the PI3K-PKB pathway

Alleviates neuronal injury

[252]

Perillaldehyde

Inhibits cGAS activity through unknown mechanism

Reduction in type-I IFN- mediated inflammation in a mouse model of Aicardi-Goutières syndrome (AGS)

[253]

TDI-6570

-

Suppresses IFN- I production

[103]

STING Inhibitors

Astin C

Inhibits STING by targeting its C-terminal activation pocket

Inhibits cytosolic DNA-trigged

gene expression

[254]

Compound 18

Inhibits STING by competing

with cGAMP

Functional inhibition of STING-mediated cytokine release

[255]

SN-011

Suppresses STING

activation by blocking CDN binding pocket

Inhibits interferon and inflammatory cytokine induction induced by 2′3′-cGAMP

[256]

C-176, C-178

Inhibits the palmitoylation of STING

Strongly reduced STING-mediated IFNβ reporter activity

[234]

C-170, C-171, H-151

Inhibits the palmitoylation of STING

Abrogation of type I IFN responses, reduction of TBK1 phosphorylation and systemic cytokine responses

[234]

NO2-FAs

Blocks STING Palmitoylation

Inhibit Release of Type I IFN

[257]

2-bromopalmitate

(2-BP)

Inhibits the palmitoylation of STING

Abolishes the type I interferon response

[258]

BPK-21, BPK-25

Inhibits the palmitoylation of STING

-

[259]

CCCP

Inhibits phosphorylation of STING and the interaction between STING and TBK-1

Inhibits STING-mediated IFN-β production

[260]

4-octyl itaconate (4OI)

Inhibits phosphorylation of STING by alkylating its cysteine sites 65, 71, 88

Represses type I IFN production

[261]

ISD017

Blocks the essential trafficking of STING from the ER to Golgi

Inhibits the expression of IFN-I and blocks pathological cytokine responses

[262]

4-HNE

Inhibits STING translocation from the ER to the Golgi

-

[263]

Palbociclib

Targets Y167 of STING to block its dimerization

Alleviates autoinflammation

[264]

SP 23

Modulates STING-degrading activities

Reduces proinflammatory cytokines and inhibited the expression of p-TBK1

[265]