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Tools & Techniques

Assembling around EnsemblinsBy Michael Flanagan

Senior WriterEnsemble Therapeutics Corp. thinks its DNA-Pro-

grammed Chemistry discovery technology is more efficient than

competing platforms in the macrocycle space. The biotech nowhas its third major partnership, a d eal withGenentech Inc. to try to raise drugsagainst challenging targets in the Rocheunits preclinical pipeline.

Ensemble will receive an undisclosedupfront payment and is eligible for mile-stones and royalties. Genentech is notdisclosing the precise targets, but did sayit wants to generate macrocyclic agentsthat address protein-protein interactions.

Macrocycles are a class of organiccompound featuring a ring structure foundin many natural products. They typically

range in size from 500-2,000 Da., makingthem larger than most small molecules butsmaller than biologics.

Ensembles DNA-Programmed Chem-istry (DPC) discovery platform synthesizesmolecules, dubbed Ensemblins, with cyclicbackbones that typically range in size from600 to 1,000 Da. (see SciBX:Science-Business eXchange, Jan. 26).

That size range is a sweet spot between small molecules andbiologics, making Ensemblins small enough to be orally availableand cell permeable, but big enough to interact with targetsagainst which small molecules have been ineffectual, accordingto Ensemble President and CEO Michael Taylor.

Ensemblins are also easier to manufacture and have a lowcost of goods than biologics, he said.

The DPC technology relies on DNA as a template to genermacrocycles using synthetic building blocks, according to C

Nick Terrett.Each template contains four to five codons so tafter four to five chemical steps we whave constructed a unique sequencebuilding blocks attached to the DNA teplate, he said.

For screening, Ensemble incubates templates in an assay containing the tended target immobilized on a solid sport. Components that have not bouare then washed off, and the templDNA of bound components is cleavamplified by PCR and sequenced to idtify which macrocycles were active.

Other companies synthesize the D

by adding base sequences after the adtion of each new synthetic building blocresulting in slower and less efficient sthesis and purification processes, sTerrett.

According to Taylor, ideal targets Ensemblins include phosphatases, p

teases and protein-protein interactions.We believe Ensemblins can take the best characterist

from small molecules and protein therapeutics and will apthem to challenging targets in our pipeline, like protein-protinteractions, where were already familiar with the biology, s

James Sabry, VP of partnering at Genentech.

We believe Ensemblins

can take the best character-

istics from small molecules

and protein therapeutics

and will apply them to chal-

lenging targets in our pipe-

line, like protein-protein

interactions, where werealready familiar with the

biology.

James Sabry, Genentech

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Genentechs R&D group focuses on oncology, immunology,neuroscience and infectious diseases.

Sabry said Genentech picked Ensemble f rom among othercompanies working on molecules in the same size rangebecause of Ensembles ability to synthetically engineer large

numbers of macrocyclic compounds for use in drug discov-ery.

Ensemble has a l ibrary of more than 4.2 mill ionmacrocycles, which it says is the largest in the industry. Inaddition, Taylor said the companys chemistry approach,which works by combining small stretches of tagged DNA viacontrolled reactions, is more modular and scalable than compet-ing technologies.

Other companies working in the space include BicycleTherapeutics Ltd., PeptiDream Inc., Ra Pharmaceuti-cals Inc.and Tranzyme Inc.

Bicycle applies phage selection to chemically constrainedcyclic peptides to identify and optimize molecules with targetspecificity and binding affinity.

PeptiDream uses transfer RNA tethered to amino acids tocreate peptide macrocycle libraries for target selection andscreening.

Ra Pharma is using in vitrodisplay technologies to producelibraries of cyclic peptidomimetics.

Tranzymes macrocycle discovery technology is based on a

synthetic chemical fragment with three recognition moietlocked in place that can be modified or replaced to optimbinding stability, permeability and potency.

Ensembles prior deals include discovery collaborations wBristol-Myers Squibb Co.in 2009 and with Pfizer Inc2010.

The biotechs most advanced in-house program consistsmacrocyclic IL-17 inhibitors in preclinical testing for auto

mune conditions. The company hopes to identify a lead candate this year and begin Phase I testing in 2014.

There are a number of anti-IL-17 mAbs in developmeincluding Eli Lilly and Co.s ixekizumab and secukinumab frNovartis AG. Both are in Phase III testing for autoimmuconditions.

COMPANIES AND OTHER INSTITUTIONS MENTIONED

Bicycle Therapeutics Ltd., Cambridge, U.K.

Bristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y.

Eli Lilly and Co. (NYSE:LLY), Indianapolis, Ind.

Ensemble Therapeutics Corp., Cambridge, Mass.

Genentech Inc., South San Francisco, Calif.

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland

PeptiDream Inc., Tokyo, Japan

Pfizer Inc. (NYSE:PFE), New York, N.Y.

Ra Pharmaceuticals Inc., Boston, Mass.

Roche (SIX:ROG; OTCGX:RHHBY), Basel, Switzerland

Tranzyme Inc. (NASDAQ:TZYM), Durham, N.C.