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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 are characterized by 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, macrocycles, such as those found in natural products, have repeatedly shown success. With their large circular backbones, macrocycles present a range of binding functionality from a pre-organized template, and as such, interact efficiently with protein surface extended binding motifs. Historically, macrocycles have been difficult to synthesize with the range of structural diversity required for modern drug discovery. Ensemble Discovery is designing and synthesizing macrocyclic Ensemblins™ that have a degree of pre-organization and present a range of binding interactions to drug discovery targets.
By applying DPC as well as conventional chemical synthesis for the creation and rapid assessment of large numbers of Ensemblins, Ensemble has identified and optimized hits against several difficult extended binding motif targets such as BCL-XL and the TNF receptor. DPC enables the controlled synthesis of large numbers of purified and analyzed synthetic macrocyclic Ensemblins. Through rapid and sensitive affinity selection experiments we have identified hit structures as well as generated an overview of structure-activity relationships (SAR). This information has provided us starting points for hit to lead optimization prosecuted using further DPC chemistry and through the conventional synthesis of individual molecules. Our most advanced Ensemblin program to date is the discovery of potent TNF antagonists.
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The Ensemblins™ fill a third structural space between small molecule drugs and more complex biological therapeutics. |
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