EPAC1 Partial Agonist Identified From Compound Cloud Custom Library

EPAC1 Partial Agonist Identified From Compound Cloud Custom Library

A collaborative screening project involving three Scottish Universities has identified a partial agonist for the cyclic AMP receptor EPAC1 from a Compound Cloud custom library.

The research involved academics from Heriot-Watt, Dundee and Glasgow universities, with the results published online by Nature Scientific Reports at the end of March. The findings detail isoform-specific agonist activity towards EPAC1 and exhibit a great example of how sequential cherry-picking can be utilised to develop small molecule tools.

The activity pathways of EPAC 1 and 2 are thought to be involved in suppressing several disease states. Present in various cells types, EPACs are switched to an active conformation on binding the second messenger molecule cyclic AMP. The open and active form is then able to bind the Ras GTPase homologues Rap1 and Rap 2 which are activated in turn to exert control over cellular activity. This process initiates a multitude of downstream pathways, including pathways thought to suppress the development of diabetes and signalling of inflammation.

The project optimised assay conditions where hits were identified by a reduction in fluorescence on their displacement of fluorescent cAMP analogue 8-NBD-cAMP from within the EPAC activation site. The primary screen gave 33 hit compounds that were tested for a dose-response effect, giving two molecules with estimated potencies 40 µM and 70 µM (I178 and I288). These two structures were then compared against the entire Compound Cloud collection to produce a further 32 structurally similar compounds, giving rise to I942 which had the greatest estimated potency at 35 µM.

Compound Cloud’s distinctive capabilities helped support this project. The researchers had complete control over the content and format of their library, selecting 5,195 drug-like compounds in the exact concentration, volume and plate setup that they required. A committed follow-up service then provided the sequential cherry-picking that discovered I942. In the same way or with even more iterations, researchers can use similarity searching to discover meaningful structure-activity relationships and increasingly potent structures.

Read the full paper at Nature Scientific Reports.

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