Exploring Macrocycles and Their Use in Targeting Protein-Protein Interactions for Drug Discovery
Nandini Kashyap:
What is so important about macrocycles in drug discovery?
Nick Terrett:
Macrocycles have a notable history in drug discovery. There are many naturally occurring macrocycles that are marketed for therapeutic uses – obvious examples include the antibiotic erythromycin, the immunosuppressing drug cyclosporine used to prevent organ transplant, and the anti-cancer agent, rapamycin. These compounds are distinguished in their ability to bind to targets such as protein-protein interactions (PPIs) that are somewhat flat and featureless, by making several interactions with ‘hot spots’ which are widely dispersed over the protein surface. To do this, they are larger than the average drug molecule; their molecular weights tend to be above 500 Daltons. Yet they have evolved to have cell membrane permeability and other drug-like properties, including oral bioavailability, which are akin to typical small molecules. They can thus access targets within cells that are out of the scope of biological drugs.
Nandini Kashyap:
If macrocycles are so suitable for tough drug discovery targets, why has interest in these molecules only recently begun to gain traction?
Nick Terrett:
Although macrocycles can possess drug-like properties, many chemists have been understandably deterred by the structural and stereochemical complexity of natural products. They are difficult to make, and any program that requires a large number of analogs would require significant synthetic effort. However, there is a growing realization that synthetic macrocycles can be crafted to possess similar high affinity and drug-like properties. In addition, an increasing body of data indicates that we no longer have to be in Lipinski ‘rule-of-five’ space to get such a profile. Being able to manage the polar surface area and the hydrogen bond donors and acceptors in these molecules is a critical determinant of membrane permeability.
Nandini Kashyap:
Can you tell us a little about your work with macrocycles and why you chose to focus on these compounds?
Nick Terrett:
When I joined my company, Ensemble Therapeutics, about 9 years ago, we had a fantastic drug discovery platform in DNA-programmed chemistry (DPC), and were looking for a way of extracting maximum value from the technology. We knew that we could readily make libraries of millions of compounds, but were intrigued that we could make macrocycles using DPC and believed this would be a highly valuable way to explore this new class of molecule. In fact, Prof. David Liu at Harvard, one of the company founders and the inventor of DPC, had already demonstrated how readily macrocycle libraries could be created. Over the last few years we have used this highly scalable process to make millions of macrocycles which we screen very quickly and efficiently against challenging drug discovery targets.
Nandini Kashyap:
You will be delivering a presentation at the upcoming 4th Annual Property-Based Drug Design in Medicinal Chemistry on macrocycles and their use in targeting protein-protein interactions. What can audience expect from it?
Nick Terrett:
Well, I will give the background to the significance of macrocycles, and why they are particular suited for challenging drug discovery targets such as PPIs. I will then talk briefly about our approach at Ensemble in using the DNA-programmed chemistry to make large libraries of synthetic macrocycles. We have used our libraries in affinity-based selection assays to find hits against many targets over recent years. I will talk about the process we apply to rapidly identify and confirm new hit molecules.
Nandini Kashyap:
Are there any successes with your approach that you are able to discuss in detail at the conference?
Nick Terrett:
We have had several successful applications of the technology to macrocycle drug discovery. I will illustrate the capabilities of this structural class with our discovery of macrocycles that bind with high affinity to the BIR2 and BIR3 domains of XIAP, a natural protein that suppresses apoptosis, or programmed cell death in cancer cells. By finding macrocycles that bind with high affinity to this intracellular target, we were able to trigger apoptosis causing regression of tumors in a xenograft mouse model. During the discovery process, we were able to use x-ray co-crystal structures to help improve the design of the macrocycles, and a consideration of the physical properties was essential in improving membrane permeability.
Speaker Bio:
Nick Terrett, Ph.D., Chief Scientific Officer, Ensemble Therapeutics Corp.
Nick Terrett was born in London, England and educated at the University of Cambridge (MA, PhD). During his career Nick has had extensive experience working as a drug discovery chemist in both the pharmaceutical and biotech sectors. Nick was lead chemist and inventor for the program that discovered sildenafil citrate (Viagra™) the world’s first oral therapy for male erectile dysfunction, and also marketed for pulmonary hypertension (Revatio™). He established Pfizer’s combinatorial chemistry group, and was also responsible for high throughput screening and the materials management groups. Following a move to the US, Nick was Senior Director and Head of Chemical Sciences at Pfizer, Cambridge MA. Since 2006 he has been Chief Scientific Officer for Ensemble Therapeutics, a drug discovery biotech company in Cambridge, MA. Nick is also an advisor for several biotech companies and the Chemical Abstracts Service of the American Chemical Society.