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by Alan M. Mathiowetz, Siegfried S. F. Leung and Matthew P. Jacobson
Macrocycles have a number of inherent advantages that improve their prospects for achieving oral bioavailability, even when their physical properties lie outside the traditional Rule-of-5 chemistry space. This chapter provides an overview of these advantages, with particular attention given to the potential for macrocycles to adopt three-dimensional conformations that overcome barriers to permeability. An overview of the relationship between physical properties and oral bioavailability is given along with a more detail description of permeability, including recent developments in using fundamental physics to predict passive permeability. A variety of orally bioavailable macrocycles is described, including both natural products and compounds discovered through medicinal chemistry. In addition, some structure property relationships are described, which were identified during the process of optimizing these macrocycles.
October 16, 2014
From the Book: Macrocycles in Drug Discovery
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Read online article by Ron Leuty, Reporter at San Francisco Business Times
Startup Circle Pharma Inc., a UCSF and UC Santa Cruz spinout devising ways to disrupt a wide variety of diseases from inside cells, will work with Pfizer Inc. on two drug programs.
The financial value of the collaboration, as well as the amount of seed funding Circle received this summer from Pfizer and Mission Bay Capital LLC, wasn’t disclosed.
The companies also didn’t specify the two targets that are central to the collaboration.
Still, the deals are huge for Circle — after all, it’s not every day that the world’s largest drug company opts to collaborate with and fund a startup. What’s more, the deal validates the San Francisco company’s coupling of synthetic chemistry with computational design algorithms to select drugs that can slip through cell membranes to attack diseases.
But the deals also are big wins for QB3, also known as the California Institute for Quantitative Biosciences, which aims to commercialize academic work out of the University of California, Berkeley, UCSF and UC Santa Cruz.
Circle’s founders — UCSF School of Pharmacy professor Matt Jacobson and Scott Lokey, a professor of chemistry and biochemistry at UC Santa Cruz — linked up with Pfizer a few years ago through one QB3 program. The company formed with the help of another QB3 program, and it assembled its business plan through yet another QB3-related endeavor.
Even Mission Bay Capital is connected to QB3, managed by QB3 director Regis Kelly and associated director Douglas Crawford, to invest in UC life sciences startups.
“This is an ideal (outcome) — from sponsored research to startup. It’s a cool model,” said Neena Kadaba, director of industry alliances with QB3. “The idea is to pull in startups that are invisible to pharma partners.”
Circle’s work centers on macrocyclic peptides, or strings of amino acids formed into circles. Those molecules potentially could address many diseases that can’t be hit today with conventional small-molecule drugs or large-molecule biologics.
Most therapies require a place on the surface of a cell where a drug can land and attach — a so-called binding site — but macrocyclic peptides can bypass binding sites by wiggling directly into cells. That permeability makes macrocycles attractive for attacking “undruggable” diseases, said Circle Pharma President and CEO David Earp, as well as cancers, fibrosis, inflammation and infection.
The challenge for several companies that have jumped into the field over the last half-dozen years is that they find a macrocycle that works against the disease in theory but ultimately can’t get the macrocycle into the cell.
Circle Pharma, Earp said, understands the physics of the molecules, how they adapt within and outside of the cell and how they interact with proteins. While macrocycles could help carry existing drugs into cells and be more effective once inside, Circle is focusing on developing new drugs — initially for Pfizer, but eventually for other partners and itself — rather than reshaping old ones.
Pfizer (NYSE: PFE) understood Jacobson and Lokey’s computational approach to macrocycles right away, Earp said. It funded the duo’s research through a QB3-Pfizer program that links drug makers and academics.
QB3 also worked with Jacobson and Lokey through another program, called Startup in a Box, to get Circle Pharma incorporated and ready to go. It also helped Jacobson and Lokey, who are QB3 faculty, apply for federal Small Business Innovation Research awards that became manna for biotech startups deserted by venture capital funders during the biotech industry’s roughly five-year financial drought that started in 2007.
Around that time, QB3’s Crawford called Earp, who left Geron Corp. (NASDAQ: GERN) after 13 years as chief legal officer, senior vice president of business development and other positions. Crawford asked if Earp would be interested in advising academics through the complexities of setting up new companies.
One of those companies would be Circle.
“The power of the technology was apparent in theory,” Earp said, “but it’s something different to take an academic project into a company environment with timetables and limited resources — sometimes more limited than the academic environment.”
Yet Circle has met those challenges and now is what Earp calls a “rational drug development company.”
Kadaba of QB3 calls Circle validation of the institute’s work to move potential therapies from lab bench to bedside. But, she added, it also shows that companies need more than an encouraging word and a pat on the head from Big Pharma.
“Startups need more than just, ‘Here’s the target and we’ll come back and be interested in two years,’” she said. “They need, ‘Here’s the data you need to generate and here’s $300,000 to go do it.’ They need pharma partners that are engaged.”
Circle Pharma, Inc., a newly created, early-stage biotechnology company, today announced that it has received seed funding from Pfizer Inc. and QB3’s seed-stage venture fund, Mission Bay Capital, LLC, and has initiated two collaborations with Pfizer to develop cell permeable macrocyclic peptide therapeutics.
“We are very pleased to have launched Circle with the backing of Pfizer and Mission Bay Capital, and to have initiated two exciting collaborative projects with Pfizer,” said David J. Earp, J.D., Ph.D., Circle’s President and CEO. “In addition to these collaborations, Circle will be undertaking development work against our own therapeutic targets. We are open to additional collaborations with partners who share our excitement in the potential of permeable macrocyclic peptides, which, we believe, could be applicable to a large number of important therapeutic targets.”
Circle’s technology is based in part on research sponsored by Pfizer through an agreement with QB3.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to provide access to therapeutic targets that are considered undruggable with conventional small molecule or biologic modalities. In particular, there is great interest in developing macrocycles to modulate protein-protein interactions, which play a role in almost all disease conditions, including cancer, fibrosis, inflammation and infection. However, the development of macrocyclic therapeutics has been limited to this point by the need for a greater understanding of how to design macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Indeed, today, most clinical programs testing macrocyclic peptides are aimed at extracellular protein targets because of the challenge of identifying cell permeable macrocycles. The ability to design potent macrocycles with inherent permeability is expected to give access to a large number of important therapeutic targets that have been out of reach to this point.
About Circle
Circle Pharma is an early stage biotechnology company applying proprietary computational design algorithms and innovative chemistry to develop cell permeable macrocycle peptide therapeutics against important clinical targets. It does this through an iterative, rational design process that deploys large virtual libraries of conformationally diverse macrocycle scaffolds selected for inherent permeability. The company was founded by Prof. Matt Jacobson, Ph.D. (U.C. San Francisco) and Prof. Scott Lokey, Ph.D. (U.C. Santa Cruz) and is headed by David J. Earp, J.D., Ph.D.
September 22, 2014, San Francisco
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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by Bockus AT, McEwen CM, Lokey RS
The structural complexity of many natural products sets them apart from common synthetic drugs, allowing them to access a biological target space that lies beyond the enzyme active sites and receptors targeted by conventional small molecule drugs. Naturally occurring cyclic peptides, in particular, exhibit a wide variety of unusual and potent biological activities. Many of these compounds penetrate cells by passive diffusion and some, like the clinically important drug cyclosporine A, are orally bioavailable. These natural products tend to have molecular weights and polar group counts that put them outside the norm based on classic predictors of “drug-likeness”. Because of their size and complexity, cyclic peptides occupy a chemical “middle space” in drug discovery that may provide useful scaffolds for modulating more challenging biological targets such as protein-protein interactions and allosteric binding sites. However, the relationship between structure and pharmacokinetic (PK) behavior, especially cell permeability and metabolic clearance, in cyclic peptides has not been studied systematically, and the generality of cyclic peptides as orally bioavailable scaffolds remains an open question. This review focuses on cyclic peptide natural products from a “structure-PK” perspective, outlining what we know and don’t know about their properties in the hope of uncovering trends that might be useful in the design of novel “rule-breaking” molecules.
May 21, 2013
Current Topics in 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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by Elena Dolghih and Matthew P. Jacobson
In order to reach their pharmacologic targets, successful central nervous system (CNS) drug candidates have to cross a complex protective barrier separating brain from the blood. Being able to predict a priori which molecules can successfully penetrate this barrier could be of significant value in CNS drug discovery. Herein we report a new computational approach that combines two mechanism-based models, for passive permeation and for active efflux by P-glycoprotein, to provide insight into the multiparameter optimization problem of designing small molecules able to access the CNS. Our results indicate that this approach is capable of distinguishing compounds with high/low efflux ratios as well as CNS+/CNS– compounds and provides advantage over estimating P-glycoprotein efflux or passive permeability alone when trying to predict these emergent properties. We also demonstrate that this method could be useful for rank-ordering chemically similar compounds and that it can provide detailed mechanistic insight into the relationship between chemical structure and efflux ratios and/or CNS penetration, offering guidance as to how compounds could be modified to improve their access into the brain.
December 2, 2012
ACS Chemical Neuroscience
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by Rand AC, Leung SS, Eng H, Rotter CJ, Sharma R, Kalgutkar AS, Zhang Y, Varma MV, Farley KA, Khunte B, Limberakis C, Price DA, Liras S, Mathiowetz AM, Jacobson MP, Lokey RS
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats. In particular, the ionization state of the peptide was examined by the incorporation of naturally occurring amino acid residues that are charged in differing regions of the gut. In addition, data was generated in a variety of in vitro assays and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed.
October 3, 2012
Medicinal Chemical Communications
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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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