RU.521

Allosteric Inhibitor of CGAS

Structure

Information

Protein target names: CGAS

Mechanism of action: Allosteric Inhibitor

Recommended in-cell concentration:
up to 1 uM

Reviewer recommended in-cell concentration: up to 5 uM

In Vitro Validations

Uniprot ID: Q8N884
Target Class: Other
Target SubClass: cyclic GMP-AMP synthase
Potency: KD, IC50
Potency Value: 36.2 nM (KD), 110 nM (IC50)
Potency Assay: ITC (KD), consumption of ATP and GTP, and the generation of cGAMP using an RF-MS
PDB ID for probe-target interaction (3D structure): 5XZG
Structure-activity relationship: yes
Target aliases:
Cyclic GMP-AMP synthase, MB21D1, C6orf150, CGAS, C ...

In Cell Validations

In Vivo Data

No in Vivo Validations

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SERP ratings and comments


SERP Ratings

In Cell Rating

(last updated: 2 Dec 2020 )

SERP Ratings

In Cell Rating

Comments:

The pursued screening hit possessed an acceptable structure but the remaining hits are questionable, including an electrophile and a PAINS compound. This could indicate that non-developable mechanisms of inhibition of possible with this protein. However, SAR investigation was largely focused on lipophilic substituents and did not include molecular matched pair analysis of polar contacts, so the specificity of binding is unclear. The kinetic analysis of the binding mode was performed with a weaker binding analogue of the proposed probe and appears to show a noncompetitive inhibition mechanism with both ATP and GTP (no change in Kmapp but clear decrease in kcat). This mechanism is not consistent with overlays of the inhibitor and substrates bound, which appear mutually exclusive, and could indicate some non-specific contribution to the biochemical inhibition. The small number of analogues tested, the lack of selectivity data, physicochemically matched negative controls and with no confirmed intracellular target engagement, means these compounds should be used with caution in cells.

(last updated: 5 Dec 2020 )