Macrocycles by the millions

CAMBRIDGE, Mass.—Ensemble Therapeutics has initiated aresearch collaboration with Boehringer Ingelheim (BI) to discover candidates ofa novel class of small-molecule drugs called macrocycles against severalhigh-value pharmaceutical targets specified by Boehringer Ingelheim.

Under the terms of the agreement, Ensemble is eligible toreceive payments of up to $186 million in milestones in the case of fullcommercial success of multiple drug products, including an upfront payment andresearch funding. In addition, Ensemble is eligible to receive royalties onfuture sales of products that arise from the collaboration. Further details ofthe agreement were not disclosed.

The collaboration will deploy Ensemble's proprietary drugdiscovery platforms, including its Ensemblin collection of about 5 millionmacrocycles, to discover and advance novel drug candidates against BoehringerIngelheim's drug targets. Synthetic macrocycles thatare readily accessible, Ensemblins also have potential for pharmacologicalactivity and good drug-like properties such as cell permeability and oralbioavailability. BI has nominated several targets of interest to whichthe Ensemblin platform will be applied, but neither the number nor theidentities of the targets is being disclosed.

"This collaboration with Boehringer Ingelheim builds onEnsemble's business strategy to partner with leading pharmaceutical companiesand further validates the wide-ranging potential of our Ensemblin drugdiscovery platforms while providing Ensemble with additional funding to advanceour own internal pipeline," says Dr. Michael D. Taylor, CEO of Ensemble.

A small number of naturallyoccurring macrocycles have been recognized for many years as beingpharmacologically active, notes Taylor.

"Several of these, such ascyclosporine and erythromycin, are efficacious drugs," he says. "However, theyare structurally very complex and difficult to synthesize or modify to improveactivity or pharmaceutical properties. Ensemblins can be efficientlysynthesized and screened by the millions using Ensemble's proprietaryDNA-programmed chemistry platform. Individual active compounds are readilyidentified and rapidly scaled-up using conventional chemistry for biochemicaland pharmacological screening."

BI will have the exclusive right to develop andcommercialize substances arising from the collaboration. The total collection of 5 million Ensemblin macrocyclesdeveloped over the past few years were the result of a number of separatelibrary campaigns.

"For each library, we haveselected a range of diverse building blocks and connected these intomacrocycles using a range of different chemistries," Taylor says. "This resultsin distinctively different macrocycle backbones between the libraries. In manycases, we have designed in protein-binding features, deliberately incorporatingstructural motifs observed in protein epitopes that bind partner proteins. Thestructure of each macrocycle is encoded in an attached unique DNA strand, sothat hit compounds are readily identified by amplifying and sequencing the DNA.There is considerable macrocycle space still available to be explored, and ourcurrent library campaign will more than double the number of Ensemblins to morethan 10 million compounds by early 2013."

Prior to its agreement with BI, Ensemble entered allianceswith Genentech, Bristol-Myers Squibb Co. and Pfizer Inc. to access Ensemble'smacrocycle libraries for purposes of affinity screening drug discovery againstdifficult-to-address targets. Ensemble's internal discovery and developmentefforts are focused on the key therapeutic areas of oncology andimmuno-inflammatory diseases, with its lead program being a small-moleculeantagonist of Interleukin-17, a cytokine implicated in multiple inflammatoryand autoimmune diseases, which is poised to enter development with an orallyactive candidate in early 2013.