Macrocycle Milestone for Ironwood Pharma
Aug17

Macrocycle Milestone for Ironwood Pharma

Ironwood Pharmaceuticals and Forest Laboratories last week announced submission of an NDA for linaclotide, a peptide macrocycle for treatment of irritable bowel syndrome (IBS). This is the first new drug application for Ironwood, a 13-year old Cambridge, MA company, and it could validate other companies’ strategies for large-ring drugs (covered recently by Carmen Drahl in C&EN). There’s an enormous potential market for this drug; by Ironwood’s count, a combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these conditions. So, how does linaclotide help IBS sufferers, um . . . go? This 14-amino acid peptide ring, taken orally, arrives at the intestinal lumen, where, according to Ironwood patent literature, it docks with a receptor enzyme called guanylate cyclase C (GC-C). The extracellular domain (part that sticks out of the cell membrane), upon binding, initiates the intracellular domain (inside the cell) to begin production of guanosine-3’, 5’-cyclic monophosphate (cGMP), a signaling molecule that induces changes in the intestinal wall. In short, cGMP prompts the intestinal surface to release chloride and bicarbonate ions into the intestinal tract, which decreases sodium uptake and increases fluid secretion (Note: interestingly, this is similar to the body’s response upon E.coli infection; a bacterial toxin called ST-peptide causes traveller’s diarrhea). In Ironwood’s own words, these physiological changes “accelerate intestinal transit,” which helps to move solid waste and decrease overall pain by acting on local nerve responses. Update (3:20PM, 8/17/11) - Changed "nearly 45 million people in the US alone suffer from IBS, yet few drugs are approved for this condition" to "combined 45 million people in the US suffer from IBS and related chronic constipation (CC), yet few drugs are approved for these...

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Ensemble Hits Macrocycle Milestone
Apr12

Ensemble Hits Macrocycle Milestone

Today, Ensemble Therapeutics announced it has developed experimental drugs with molecular structures containing a large ring, which the company calls Ensemblins, against one of 8 key drug targets laid out in a 2009 agreement with Bristol-Myers Squibb Company (BMS). As a result, the drug development program will be handed off to BMS and Ensemble will receive a milestone payment. Neither the drug target nor the milestone payment amount have been disclosed. I first became acquainted with Ensemble in 2008, when I wrote about a symposium extolling the potential benefits of compounds containing rings of 12 or more atoms, also known as macrocycles, in drug discovery. These molecules are larger in size than traditional small molecule drugs, but they can increase the strength of a binding interaction at a desired target, or even make it possible to target proteins in the body that traditional small molecule drugs can't. Some macrocylic drugs are already on the market, such as the antibiotic erythromycin and the immunosuppressant rapamycin. In 2009, I focused on one of Ensemble's proprietary drug discovery programs, but since then the company has partnered with both Pfizer and BMS, developing macrocyclic Ensemblins for tough-to-hit targets. In reporting the 2009 story, I learned that Ensemble's discovery platform, which is based on chemistry carried out in company founder David R. Liu's lab at Harvard University, uses DNA to guide production of thousands of different macrocycles at a time, and then tests the macrocycles' ability to disrupt biologically relevant interactions between proteins. Drugmakers tend to develop biologic drugs to tackle these so-called protein-protein interactions, because these interactions don't usually have the kind of well-defined pockets a small molecule can wedge its way into- they come together more like two marshmallows as opposed to two LEGO bricks. Given that knowledge I asked medicinal chemist Michael D. Taylor, Ensemble's president and CEO, about the nature of the 8 key targets in the BMS collaboration. "Macrocycles are useful for a variety of different targets," Taylor says. "We've always thought that protein-protein interactions are an area or particular importance and our partners have emphasized protein-protein interactions within the collaborations that we have, so it's fair to say that the vast majority of the targets fall in that area." Ensemble's press release about the milestone also mentions that the company has made improvements to its platform to boost output as well as druglike qualities in its libraries of macrocycles. I asked Ensemble's chief scientific officer Nick K. Terrett, also a medicinal chemist, to elaborate. He says the changes come in two areas- first, to the company's DNA-guided discovery platform, and second, to the organic chemistry used to make...

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