New synthesis and screening technologies and the allure of access to previously undruggable targets are driving an explosion of new company formation and deal-making around macrocycles and constrained peptides.
While it remains to be seen whether the in vitro promise of these platforms will translate into viable drug candidates, the clinical successes of macrocyclic natural products provide tantalizing hints of what could be achieved by the systematic exploration of this compound class.
Macrocycles may be capable of hitting new classes of targets because their ring structure causes them to behave differently than most small molecules.
Macrocycles are chemically defined by a ring structure of at least 12 atoms. They are typically 500-2,000 daltons in size. In contrast, most small molecules weigh less than 500 daltons, which has been considered the upper limit for a compound to be cell permeable and orally bioavailable.
"The easy targets have now been done; enzymes and GPCRs largely have been addressed through small molecules," said Ensemble Therapeutics Corp. CSO Nick Terrett."Protein-protein interactions with large surface areas are very difficult to address with small molecules, and macrocycles are a very effective way of getting to a size that allows enough interaction with the protein."
A similar approach is to create constrained peptides by artificially linking linear peptides into specific structures possessing improved drug-like properties including cell permeability.
Ensemble is one of at least 12 biotechs developing platforms for synthesizing or screening macrocycles and constrained peptides (see "Building Cycles," A8).
As a group, these companies are enjoying a rush of attention from big pharma - there have been at least 27 discovery partnerships with biopharma partners in the last five years (see "Cycle Shops," A12).
"There is no doubt that within the last 3-4 years it has been a lot easier to get pharma's attention from a collaboration standpoint," said Tranzyme Inc. VP of IP and operations Mark Peterson. Tranzyme partnered its macrocycle discovery platform with Bristol-Myers Squibb Co. in 2009.
Indeed, collaboration looks to be essential to solving the puzzle of cell access. At this point, all the lead programs disclosed thus far are aiming at extracellular targets.
The model macrocyclic drug that inspired these development efforts is cyclosporine, a fungal-derived natural product developed as an immunosuppressant more than 30 years ago by Sandoz AG