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Ensemble Discovery is using DNA-Programmed Chemistry™ (DPC™) to discover drug candidates against historically challenging targets such as protein-protein interactions, phosphatases, and proteases. Such targets have the feature of an “extended binding motif” through which they interact with their partner or substrate. Whereas traditional medicinal chemistry approaches have been markedly unsuccessful in generating drugs against these targets, certain natural products, such as macrocycles, have shown some success. With their large circular backbones, macrocycles are natural product-like compounds that present a range of binding functionality from a pre-organized template, and as such, interact efficiently with extended binding motifs. Historically, macrocycles have been difficult to synthesize with the range of structural diversity required for modern drug discovery. Ensemble Discovery is investigating the activity of 'Ensemblins' large molecules which like macrocycles have a degree of pre-organization and that present a range of binding interactions to drug discovery targets.
By applying DPC for the creation and rapid assessment of large numbers of Ensemblins, Ensemble can readily identify and optimize hits against difficult extended binding motif targets. DPC enables the controlled synthesis of large numbers of purified and analyzed synthetic macrocyclic Ensemblins. Through rapid and sensitive affinity selection experiments we are able to identify hit structures as well as generate an overview of structure-activity relationships (SAR). This information gives us starting points for hit to lead optimization which can be prosecuted using further DPC chemistry or through the conventional synthesis of individual molecules.
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Ensemble’s Programmed Macrocycles™ fill a third structural space between small molecule drugs and more complex biological therapeutics. |
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