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 discrete macrocycles (macrocycles sans DNA) for further testing. In the first area, the company has made very specific improvements in how they do chemistry on DNA, which has increased speed and has lowered cost per compound synthesized from just under a dollar in 2009 to nine cents today. They’ve also designed a new scheme for programming a chunk of DNA to encode specific bits of a macrocycle.
In the second area, making discrete compounds without DNA, the operation usually involves solid phase chemistry. Here, the team has changed reagents to cut costs and improve yields.
Terrett and Taylor emphasize that Ensemble’s role isn’t just hit-finding. The new improvements to both parts of the platform help Ensemble start with the most diverse set of macrocycles possible, they say. They also help chemists take hits that emerge from screening those diverse macrocycles and develop them into leads with druglike properties, such as oral bioavailability-the ability to be absorbed in the body when taken orally. “We drove all the chemistry up to this point,” Taylor says. “Now BMS can pick up and run with it.”
More reading: “The exploration of macrocycles for drug discovery — an underexploited structural class”,
Driggers, Terrett, et al, Nature Rev. Drug Disc., DOI: 10.1038/nrd2590.
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