Table 1 Representative tool cGAS inhibitors for mechanistic studies, in vitro and in vivo, and as lead compounds for developing therapies to treat neurodegenerative diseases
From: Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Organization | Compounds | Activity, properties, and comments |
|---|---|---|
Rockefeller University | RU.521 [107] | Inhibits mouse cGAS with sub micromolar activity in cell-free assays and cGAS-dependent IFN induction in cellular assays. Likely brain impermeable. Suitable as experimental compounds to test in vitro |
Rockefeller University/Tri-Institutional Therapeutics Discovery (TDI) | TDI-6570 [109] | Inhibits mouse cGAS with low nanomolar activity and human cGAS with a high nanomolar activity in cell-free assays, and cGAS-dependent IFN induction in mouse microglial BV2 cells at low micromolar concentration (IC50 = 1.64 µM) [47], but not in human macrophage THP-1 dual cells (IC50 > 40 µM) [116]. Brain permeable but quickly metabolized [47, 118]. Suitable as experimental compounds to test in vitro and in vivo using mouse models [47] |
Rockefeller University/TDI | G-140 (TDI-8077), G-150 (TDI-8087), TDI-8246 [109], and TDI compounds [67, 68, 116, 117] | TDI-6570 analogs. Possess low nanomolar activity against h-cGAS and weakly to m-cGAS in cell-free assays and low micromolar concentrations in THP-1 dual cells. compounds. 67 and 68 show sub micromolar inhibition of h-cGAS in cell-free assays and similar activity on cGAMP production in THP-1 cells [119]. Suitable as experimental compounds to test in vitro using human iPSC-derived cells and development for therapies to treat neurodegenerative diseases |
Ventus Therapeutic | Compound 102 [120] | Modified TDI-6570 analogs. Possess low nanomolar IC50 in cell-free assay. Shows superior activity than TDI-6570 in THP-1 dual cells. Suitable as experimental compounds to test in vitro using human iPSC-derived cells and development for therapies to treat neurodegenerative diseases |
Weill Cornell Medicine | ADI034-4, ADI046-3, ADI051-5 [118] | Benzofuran and benzothiophene derivatives. Possess inhibitory effects on cGAS activity with low to high micromolar activity. ADI034-4 shows activity comparable to TDI 8246, in cell free assay [118] |