12:00 AM
Nov 15, 2012
 |  BC Innovations  |  Cover Story

Bringing macrocycles full circle

The opportunity afforded by macrocycles and constrained peptides to open up vast new therapeutic real estate is rivaled only by the challenge of puzzling out the basic science underlying these molecules.

Now, a think tank convened by SciBX has outlined an agenda for how to shed light into this black box, potentially providing a path to systematically identify macrocycle- or constrained peptide-based medicines that would combine the cell permeability and oral bioavailability of small molecules with the potency and selectivity of mAbs.

Successfully implementing the agenda may allow drug developers to more readily modulate challenging targets such as intracellular protein-protein interactions, which would open up the pharmaceutical landscape to a wide range of new targets that are currently undruggable.

Solving for the unknowns also would keep the momentum behind the surge of efforts by biotech and pharma companies to create footholds in the macrocycle space and would maintain investor interest.

The SciBX think tank, comprising academic, biotech, pharma and VC stakeholders, discussed the state of the macrocycle space at the first SciBX Summit on Innovation in Drug Discovery & Development in Boston in September, which was attended by key opinion leaders in the macrocycle and constrained peptide community (see Box 1, "SciBX innovation summits launched").

During the summit, participants identified four areas of science in which work is needed to enable drug innovation. Three of them-pharmacokinetics, cell permeability and oral bioavailability-aim to create an understanding of the rules that govern the behavior of macrocycles and thus enable developers to better identify drug-like compounds. The fourth one tackles the issue of targeting.

First, improving pharmacokinetics, particularly serum half-life and tissue exposure, will be critical to effectively modulate extracellular and intracellular targets and make macrocycles commercially competitive.

Second, cracking the code for cell permeability was pegged as a critical advance needed to propel the field forward. Most of the 40 or so existing macrocycle drugs are naturally occurring or very close analogs of naturally occurring molecules. Many of these macrocycle drugs enter cells via passive diffusion, but how they do so is not well understood.

Even less is known about active transport via endocytosis, although this mode of cell permeability will almost certainly be required for larger members of the macrocycle class to get into cells.

Third, achieving oral bioavailability would broaden the range of indications and targets that macrocycles and constrained peptides could address.

The fourth area is the need for a more detailed understanding of how macrocycles engage their targets. This would enable the selection of targets best suited to the properties of macrocycles and constrained peptides.

Strategic target selection for the current generation of macrocycles-which differ from most existing macrocycle drugs in that they are identified from synthetic libraries or by rational design rather than derived from natural compounds-will be necessary to provide proof of principle for this new therapeutic modality, which would give venture and public equity investors incentives to fund second-generation drugs.

Summit participants noted that many of these essential insights do not exist because the basic biology has been in areas not prioritized by government funders and academic scientists. After identifying the translational hurdles, the SciBX think tank identified action items that would enable progress across the various macrocycle platforms.

To start, the group called for massive parallel screening combined with computational approaches to interrogate both existing macrocycle drugs and other macrocycles and constrained peptides to help discover the rules of passive cell permeability.

An additional benefit to understanding the rules would be the ability to bias screening libraries so they contain more molecules likely to be cell permeable or have other desired pharmacological properties.

In the absence of rules that ultimately will be revealed by systematic studies, phenotypic screening provides an empirical approach for discovering cell-permeable macrocycles.

Next, the think tank recommended focusing more basic research on understanding active cellular transport, which may most effectively open up intracellular target space for larger members of the macrocycle class.

Then, the working group recommended the creation and validation of benchmark molecules, which would make it easier for researchers to assess the quality and applicability of new research.

Finally, the group concluded that much of this research should be done in the precompetitive setting because most of the work does not fit neatly into either conventional academic research or the corporate world.

According to think tank member Spiros Liras, VP of cardiovascular, metabolic and endocrine medicinal chemistry at Pfizer Inc., "The idea of promoting the concept of industry-academic collaboration to proliferate knowledge in this area is spot on. A single organization or entity will not be able to deliver this by itself. Partnerships between industry and academia, and finding ways for funding agencies to promote this, will be critical."

In addition to Liras, the summit task force consisted of Bruce Booth, Barry Morgan, Patrick Reid, Tomi Sawyer and Gregory Verdine.

Booth is a partner at Atlas Venture and sits on the board of phage display-based macrocycle company Bicycle Therapeutics Ltd.; Morgan is VP of molecular discovery research at GlaxoSmithKline plc; Reid is cofounder and CSO of the in vitro display-based macrocycle company PeptiDream Inc.; Sawyer is CSO and SVP of drug discovery and innovative technologies at Aileron Therapeutics Inc., which is developing stapled peptides, or a-helical peptides constrained by a hydrocarbon linker; and Verdine is a professor in the Department of Chemistry and Chemical Biology and the Department of Stem Cell and Regenerative Biology at Harvard University, a founder of Aileron and a venture partner at Third Rock Ventures.

The backdrop

Macrocycles, including cyclic small molecules or peptides and closely related chemically constrained peptides, are typically 500-2,000 Da in size and thus fall between small molecules and biologics.

Cyclosporine illustrates the potential of the macrocycle class. The immunosuppressant is a 1,200 Da cyclic peptide that is orally bioavailable and targets an intracellular protein. For small molecules, 500 Da typically is considered an upper limit for reliably achieving cell permeability and oral bioavailability.

However, in the 40 years since the discovery of cyclosporine, efforts to systematically identify cyclosporine-like molecules have had limited success.

The area has seen a surge in interest over the last five years based on the development of new approaches for synthesizing and screening macrocycles. This scientific progress has fueled a burst of business activity. There are at least 12 biotech companies in the space, of which almost half were founded in the last 5 years.

Collectively, these companies have entered into 27 discovery partnerships over the same period (see "Recent company and partnership formation trends in the macrocycle space").

Thus far, the initial crop of next-generation macrocycles from these companies are nearly all directed against targets outside the cell. For more details on the platforms, companies and deals in the macrocycle space, see the linked BioCentury article, "Excited about cycling."

The buzz

If macrocycles are to live up to their promise, the real impact will be through the intracellular targets for which the transformational potential is greatest. Indeed, the excitement surrounding macrocycles rests on the hope that this class of molecules will hit targets that are inaccessible to small molecules and biologics.

"As a biotech sector, we've launched a bunch of companies over the last five years. The possibility that these platforms will open up novel targets is the many-million-dollar question that a lot...

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