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Macrocycles by the millions
December 2012
by Lloyd Dunlap  |  Email the author


CAMBRIDGE, Mass.Ensemble Therapeutics has initiated a research collaboration with Boehringer Ingelheim (BI) to discover candidates of a novel class of small-molecule drugs called macrocycles against several high-value pharmaceutical targets specified by Boehringer Ingelheim.  
Under the terms of the agreement, Ensemble is eligible to receive payments of up to $186 million in milestones in the case of full commercial success of multiple drug products, including an upfront payment and research funding. In addition, Ensemble is eligible to receive royalties on future sales of products that arise from the collaboration. Further details of the agreement were not disclosed.  
The collaboration will deploy Ensemble's proprietary drug discovery platforms, including its Ensemblin collection of about 5 million macrocycles, to discover and advance novel drug candidates against Boehringer Ingelheim's drug targets. Synthetic macrocycles that are readily accessible, Ensemblins also have potential for pharmacological activity and good drug-like properties such as cell permeability and oral bioavailability. BI has nominated several targets of interest to which the Ensemblin platform will be applied, but neither the number nor the identities of the targets is being disclosed.
"This collaboration with Boehringer Ingelheim builds on Ensemble's business strategy to partner with leading pharmaceutical companies and further validates the wide-ranging potential of our Ensemblin drug discovery platforms while providing Ensemble with additional funding to advance our own internal pipeline," says Dr. Michael D. Taylor, CEO of Ensemble.
A small number of naturally occurring macrocycles have been recognized for many years as being pharmacologically active, notes Taylor.
"Several of these, such as cyclosporine and erythromycin, are efficacious drugs," he says. "However, they are structurally very complex and difficult to synthesize or modify to improve activity or pharmaceutical properties. Ensemblins can be efficiently synthesized and screened by the millions using Ensemble's proprietary DNA-programmed chemistry platform. Individual active compounds are readily identified and rapidly scaled-up using conventional chemistry for biochemical and pharmacological screening."
BI will have the exclusive right to develop and commercialize substances arising from the collaboration. The total collection of 5 million Ensemblin macrocycles developed over the past few years were the result of a number of separate library campaigns.
"For each library, we have selected a range of diverse building blocks and connected these into macrocycles using a range of different chemistries," Taylor says. "This results in distinctively different macrocycle backbones between the libraries. In many cases, we have designed in protein-binding features, deliberately incorporating structural motifs observed in protein epitopes that bind partner proteins. The structure of each macrocycle is encoded in an attached unique DNA strand, so that hit compounds are readily identified by amplifying and sequencing the DNA. There is considerable macrocycle space still available to be explored, and our current library campaign will more than double the number of Ensemblins to more than 10 million compounds by early 2013."  
Prior to its agreement with BI, Ensemble entered alliances with Genentech, Bristol-Myers Squibb Co. and Pfizer Inc. to access Ensemble's macrocycle libraries for purposes of affinity screening drug discovery against difficult-to-address targets. Ensemble's internal discovery and development efforts are focused on the key therapeutic areas of oncology and immuno-inflammatory diseases, with its lead program being a small-molecule antagonist of Interleukin-17, a cytokine implicated in multiple inflammatory and autoimmune diseases, which is poised to enter development with an orally active candidate in early 2013.
Code: E1211224



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