Circle Pharma, Inc., today announced that co-founder Prof. Matthew Jacobson has been appointed Chair of the UCSF Department of Pharmaceutical Chemistry.
“This is a terrific recognition of Matt’s exceptional accomplishments as a scientist and his passionate commitment as an educator,” said David J. Earp, JD, PhD, Circle’s President and CEO. “We are very appreciative of the guidance and leadership that our two co-founders – Matt Jacobson and Scott Lokey – continue to provide to Circle.”
Prof. Jacobson’s work at UCSF has focused on understanding the complex interactions of drugs and proteins and the implications of the underlying molecular dynamics for biology and drug discovery. In addition to his founding role in Circle, Prof. Jacobson was also a co-founder of Global Blood Therapeutics (NADAQ:GBT) and serves on the Scientific Advisory Board of Schrodinger, LLC. He has authored more that 140 publictions and has served on the editorial boards of eight journals. Prof. Jacobson joined the UCSF faculty in 2002. He earned a PhD in chemistry from the Massachusetts Institute of Technology, and did his postdoctoral work at Oxford and Columbia.
About Circle Pharma
Founded by computational chemist Prof. Matthew Jacobson (UC San Francisco) and peptide chemist Prof. Scott Lokey (UC Santa Cruz), and seed funded by Pfizer and Mission Bay Capital in 2014 and ShangPharma Investment Group Limited in 2015, Circle Pharma is developing a new paradigm for macrocycle drug discovery. Circle’s technology facilitates the design and synthesis of intrinsically cell- permeable macrocycles that can address both intra- and extra-cellular therapeutic targets, and can be delivered by oral administration. Circle’s macrocycle development platform is applicable across a wide range of serious diseases; the company is initially focusing its internal development efforts on intracellular protein-protein interactions that are key drivers in cancer.
January 19, 2016, South San Francisco
Circle Pharma, Inc., today announced that it has extended its seed funding round with an investment from ShangPharma Investment Group Limited. In conjunction with this investment, Circle has relocated to office and laboratory space in South San Francisco.
“The addition of laboratory operations to our computational chemistry platform marks the next stage of Circle’s development,” said David J. Earp, J.D., Ph.D., Circle’s President and CEO, “and we have now initiated work on Circle’s internal pipeline of macrocycle therapeutics.”
“We have selected several intracellular protein-protein interactions (“PPIs”) that play key roles in oncology as our first target group. The clinical and commercial potential of this target class is well recognized but it has proven largely intractable to small molecule drugs since these are too small to disrupt the dispersed molecular interactions typical of PPIs. And, while macrocyclic peptides are large enough to disrupt those interactions, permeability challenges – getting macrocycles into cells – have so far limited progress in this promising drug class. Circle’s ability to design intrinsically cell permeable macrocycles gives us a unique opportunity to develop first-in-class drugs against these high value drug targets.”
Working with a panel of renowned oncology experts, Circle selected its first PPI target group based on criteria including the biological validation of the target’s role as a driver of cancer, unmet clinical need and availability of structural information on the PPIs involved. This first target group includes a balance of well established targets such as PPIs in the Wnt/beta-catenin pathway, and emerging targets such as PPIs involved in epigenetic regulation.
Circle initiated operations in 2014 with seed funding from Pfizer and Mission Bay Capital. Circle deployed that first seed funding to build its computational design platform and to support its ongoing collaborative work with Pfizer. Circle’s new investor, ShangPharma Investment Group Limited, is part of the ShangPharma Group which includes the full service CRO ChemPartner. Circle will work with ChemPartner to build physical libraries of conformationally diverse, cell permeable macrocycles which Circle will integrate into its macrocycle drug development platform.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to provide access to the large proportion of therapeutic targets (estimated at up to 80%) 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. As a result, most clinical-stage macrocyclic peptide drugs address extracellular protein targets because of the challenge of identifying cell permeable macrocycles. The ability to design potent macrocycles with intrinsic 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 Pharma
Founded by computational chemist Prof. Matthew Jacobson (UC San Francisco) and peptide chemist Prof. Scott Lokey (UC Santa Cruz), and seed funded by Pfizer and Mission Bay Capital in 2014, Circle Pharma is developing a new paradigm for macrocycle drug discovery. Circle’s technology facilitates the design and synthesis of intrinsically cell-permeable macrocycles that can address both intra- and extra- cellular therapeutic targets, and can be delivered by oral administration. Circle’s macrocycle development platform is applicable across a wide range of serious diseases; the company is initially focusing its internal development efforts on intracellular protein-protein interactions that are key drivers in cancer.
January 7, 2016, South San Francisco
by Andrew T. Bockus, Joshua A. Schwochert, Cameron R. Pye, Chad E. Townsend, Vong Sok, Maria A. Bednarek, and R. Scott Lokey
It is well established that intramolecular hydrogen bonding and N-methylation play important roles in the passive permeability of cyclic peptides, but other structural features have been explored less intensively. Recent studies on the oral bioavailability of the cyclic heptapeptide sanguinamide A have raised the question of whether steric occlusion of polar groups via β-branching is an effective, yet untapped, tool in cyclic peptide permeability optimization. We report the structures of 17 sanguinamide A analogues designed to test the relative contributions of β-branching, N-methylation, and side chain size to passive membrane permeability and aqueous solubility. We demonstrate that β-branching has little effect on permeability compared to the effects of aliphatic carbon count and N-methylation of exposed NH groups. We highlight a new N-methylated analogue of sanguinamide A with a Leu substitution at position 2 that exhibits solvent-dependent flexibility and improved permeability over that of the natural product.
August 26, 2015
Journal of Medicinal Chemistry
Read online article
by Christopher L Ahlbach, Katrina W Lexa, Andrew T Bockus, Valerie Chen, Phillip Crews, Matthew P Jacobson & R Scott Lokey
Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane permeabilities of 39 cyclic peptide natural products, and interpret the results using a computational permeability prediction algorithm based on their known or calculated 3D conformations. We found that the permeabilities of these compounds, measured in a parallel artificial membrane permeability assay, spanned a wide range and demonstrated the important influence of conformation on membrane permeability. These results will aid in the development of these compounds as a viable drug paradigm.
June 12, 2015
Future Science
Read online article
by Joshua Schwochert, Rushia Turner, Melissa Thang, Ray F Berkeley, Alexandra R Ponkey, Kelsie M. Rodriguez, Siegfried S F Leung, Bhagyashree Khunte, Gilles Goetz, Chris Limberakis, Amit S. Kalgutkar, Heather Eng, Michael J. Shapiro, Alan M. Mathiowetz, David A. Price, Spiros Liras, Matthew P. Jacobson, and R. Scott Lokey
The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3-fold. Additionally, the conformational impact of peptoid substitutions within a β-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality.
June 5, 2015
ACS Publications – Organic Letters
Read online article
by Andrew T. Bockus, Katrina W. Lexa, Cameron R. Pye, Amit S. Kalgutkar, Jarret W. Gardner, Kathryn C. R. Hund, William M. Hewitt, Joshua A. Schwochert, Emerson Glassey, David A. Price, Alan M. Mathiowetz, Spiros Liras, Matthew P. Jacobson, and R. Scott Lokey
Cyclic peptide natural products contain a variety of conserved, nonproteinogenic structural elements such as d-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements impact the ADME properties of these hybrid molecules, especially their ability to cross cell membranes and avoid metabolic degradation. Here we report the synthesis of cyclic hexapeptide diastereomers containing γ-amino acids (e.g., statines) and systematically investigate their structure–permeability relationships. These compounds were much more water-soluble and, in many cases, were both more membrane permeable and more stable to liver microsomes than a similar non-statine-containing derivative. Permeability correlated well with the extent of intramolecular hydrogen bonding observed in the solution structures determined in the low-dielectric solvent CDCl3, and one compound showed an oral bioavailability of 21% in rat. Thus, the incorporation of γ-amino acids offers a route to increase backbone diversity and improve ADME properties in cyclic peptide scaffolds.
May 7, 2015
Journal of Medicinal Chemistry
Read online article
by Hewitt WM, Leung SS, Pye CR, Ponkey AR, Bednarek M, Jacobson MP, Lokey RS
Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered “undruggable” by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side-chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds toward development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.
January 21, 2015
Journal of the American Chemical Society
Read online article
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
Read online article
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