RU.521
Allosteric Inhibitor of CGAS
Structure
In Cells
In Model Organisms
Probe RU.521 is in the process of SERP review.
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SERP ratings and comments
SERP Ratings
(last updated: 2 Dec 2020 )
SERP Ratings
SERP 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 )