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
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
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.
The need for unprecedented medicinal
chemistry innovation is not an exaggeration, as there are significant hurdles
to overcome before reaching the ultimate goal of orally bioavailable and
cell-permeable macrocycle drugs against new targets.
Because of the myriad challenges in
achieving cell permeability, the disclosed preclinical programs from macrocycle
companies are predominantly directed against extracellular targets.
Point of entry
Of the many pharmacological properties
of macrocycles that are not well understood, cell permeability is the central
issue for systematically unlocking intracellular targets. And much of what
dictates cell permeability is completely unknown.
Oral bioavailability is an even higher
hurdle than cell permeability. It requires that a molecule is stable in the
digestive track and passes through the endothelial cell barrier of the
intestine before being exposed in the portal vein to the liver, where it must
avoid metabolism or excretion to enter the bloodstream.
Even as the cell permeability and oral
bioavailability issues are being addressed, it is unclear how best to select
Having laid out the issues,
participants at the SciBX summit proposed a variety of initiatives with
the express goal of providing answers and solutions.
the (active) uptake
Another action item identified at the
summit would be to target research funding toward gaining a mechanistic
understanding of endocytosis.
A final opportunity identified at the
summit would be for companies and academics to contribute benchmark molecules
that could be made openly available to the community through a repository.
These macrocycles would span the diversity of chemical structures and have
well-characterized and validated mechanisms of cell uptake and functional
Much of the progress needed to push the
macrocycle field forward may best be done precompetitively-and some of the
actions suggested at the SciBX summit may only be achievable if academics
and companies collaborate in the open.
Kotz, J. SciBX 5(45); doi:10.1038/scibx.2012.1176
Published online Nov. 15, 2012
1. White, T.R. et al.
Nat. Chem. Biol. 7, 810-817 (2011)
2. Guimarães, C.R.W. et al.
J. Chem. Inf. Model. 52, 882-890 (2012)
AND INSTITUTIONS MENTIONED
Aileron Therapeutics Inc., Cambridge, Mass.
Amgen Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.
Atlas Venture, Cambridge, Mass.
Bicycle Therapeutics Ltd., Cambridge, U.K.
BioDuro LLC, Beijing, China
Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass.
Boston University, Boston, Mass.
Dana-Farber Cancer Institute, Boston, Mass.
Ensemble Therapeutics Corp., Cambridge, Mass.
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.
Harvard University, Cambridge, Mass.
Ipsen Group (Euronext:IPN; Pink:IPSEY), Boulogne-Billancourt,
MedImmune LLC, Gaithersburg, Md.
PeptiDream Inc., Tokyo, Japan
Pfizer Inc. (NYSE:PFE), New York, N.Y.
PPD LLC, Wilmington, N.C.
Ra Pharmaceuticals Inc., Cambridge, Mass.
(Euronext:SAN; NYSE:SNY), Paris, France
Sofinnova Ventures, Menlo Park, Calif.
Takeda Pharmaceutical Co. Ltd. (Tokyo:4502), Osaka, Japan
Third Rock Ventures, Boston, Mass.
Vertex Pharmaceuticals Inc. (NASDAQ:VRTX), Cambridge, Mass.