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by Fabrizio Giordanetto and Jan Kihlberg
Macrocycles are ideal in efforts to tackle “difficult” targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Å2. Moreover, insight from a group of “de novo designed” oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.
August 28, 2013
Journal of Medicinal Chemistry
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Macrocycles and constrained peptides, generally defined as cyclic small molecules or peptides of 500–2,000 Da, have undergone a rebirth over the last five years in drug discovery, due mainly to the introduction of new approaches for their synthesis and screening. This scientific progress has fueled a burst of business activity, with at least 12 biotech companies in the space, of which almost half were founded in the last 5 years.
This special collection from SciBX: Science-Business eXchange provides an overview of the state of the field from both the scientific and the business perspective.
First, in a SciBX Analysis, a roadmap for progress across various platforms is laid out by the participants at a recent SciBX Summit on macrocycles and constrained peptides. The article identifies four areas of science in which work is needed to enable innovation in the field: pharmacokinetics, cell permeability, oral bioavailability and target engagement to develop more drug-like compounds and streamline drug discovery.
This Analysis is complemented by a BioCentury Product Discovery and Development piece that provides a comprehensive overview of the competitive landscape by laying out the players in the field, their partnerships and the status of their most advanced programs.
Next, we provide an introduction to an interactive dashboard produced by Relay Technology Management that allows users to explore trends in grants, publications, company pipelines, transactions and IP relevant to macrocycles and constrained peptides. Relay TM is a strategic partner of Nature Research.
This is followed by a Review by White and Yudin that revisits the latest developments in peptide macrocyclization strategies. The cyclization of macrocycles using traditional chemical synthesis approaches has faced enormous challenges due to steric constraints and the unwieldiness of small and large precursors. But recently, new solutions have emerged, including versatile platforms for macrocycle library generation that open a myriad of new opportunities for generating synthetic macrocycles. A second SciBX Analysis specifically explores the technical and commercial possibilities that may open up based on a new method for creating large libraries of N-methylated peptide macrocycles developed by Suga and collaborators.
Finally, an article by Stewart et al. illustrates the potential of a particular class of constrained peptides called stapled peptides as therapeutic agents. Harnessing the binding precision of stapled peptides, the authors were able to design a highly specific inhibitor of MCL-1, a critical survival factor in a wide range of human cancers.
The Analyses, Reviews and Articles presented here provide a broad overview of the scientific and business status of the field and some examples of specific technological advances that are but a small sample of the possibilities to come.
We acknowledge the support of Aileron Therapeutics Inc., PolyPeptide Group, Polyphor Ltd. and Lanthio Pharma B.V. in producing this collection. Nature Research and BioCentury Publications Inc. have sole responsibility for editorial content
April 2013
Science-Business eXchange
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Macrocycles in New Drug Discovery
by Jamie Mallinson and Ian Collins
The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of ‘molecular obesity’, functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.
August 2, 2012
Future Medical Chemistry
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