March 17, 2020
South San Francisco, CA, March 17, 2020, — Circle Pharma, Inc., a macrocycle drug discovery and development company focused on intractable cancer targets, today announced that it has raised $45 million in a Series B financing.
The financing was led by The Column Group, with participation by Nextech Invest. All investors from the prior round – ShangPharma, LifeForce Capital, and the Berkeley Catalyst Fund – joined the financing.
In conjunction with the financing, Peter Svennilson, founder and managing partner of The Column Group, and Thilo Schroeder, Ph.D., partner at Nextech Invest were appointed to the board. John Josey, Ph.D., formerly President and CEO of Peloton Therapeutics, was appointed to the board as Chairman.
Proceeds from the investment will be used to advance Circle’s work to develop inhibitors of Cyclin A and Cyclin E, and to expand the company’s pipeline.
“We are delighted to have these premier life science investors supporting our Series B financing” said David J. Earp, J.D., Ph.D., Circle’s President and CEO. “With this strong backing, we will expand our team, drive our cyclin targeted programs towards the clinic, and apply our macrocycle platform to additional intractable targets.”
Circle’s new board appointments:
Peter Svennilson is the founder and managing partner of The Column Group. He was the chairman of Aragon Pharmaceuticals (acquired by Johnson & Johnson) and Seragon Pharmaceuticals (acquired by Roche / Genentech) and was a board director of Gritstone Oncology, NGM Biopharmaceuticals, Immune Design and Constellation Pharmaceuticals. He is currently a board director of ORIC Pharmaceuticals, Ribon Therapeutics and Carmot Therapeutics.
Thilo Schroeder, Ph.D., is a partner at Nextech Invest, a Zurich-based oncology-focused investment firm. He previously served on the board of Peloton Therapeutics (acquired by Merck) and Blueprint Medicines. He is currently a board director at IDEAYA Biosciences, Revolution Medicines, PMV Pharma, Silverback Therapeutics and a board observer at Black Diamond Therapeutics.
John Josey, Ph.D., served as the President, Chief Executive Officer, and member of the Board of Directors at Peloton Therapeutics from 2013 until its acquisition by Merck in 2019. From 2011 to 2013, he was President and Chief Scientific Officer at Peloton, and from 1998 to 2011, Vice President of Discovery Chemistry at Array Pharma.
The continuing members of Circle’s board of directors are Walter H. Moos, Ph.D., CEO of ShangPharma Innovation and Managing Director of Pandect Bioventures, Matthew P. Jacobson, Ph.D., Circle Pharma co-founder, chair of the department of pharmaceutical chemistry at U.C. San Francisco and also co-founder of Global Blood Therapeutics, Relay Therapeutics and Cedilla Therapeutics, and David J. Earp, J.D., Ph.D., President and Chief Executive Officer of Circle Pharma.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. 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 development efforts on intracellular protein-protein interactions that are key drivers in cancer. Its lead program targets cyclins A and E, which are part of the regulatory machinery that controls the progression of cells through the cell growth and division cycle. Inhibiting cyclins A and E has been shown to be synthetically lethal in cancers that carry mutations causing dysregulation of the Rb pathway.
More information: www.circlepharma.com
Contact: info@circlepharma.com
Read original article at Business Wire
Read original article at Business Wire
October 8, 2019
SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Circle Pharma, Inc. is delighted to congratulate Dr. Kaelin, on having been jointly awarded the 2019 Nobel Prize in Physiology or Medicine with co-recipients Sir Peter J. Ratcliffe of Oxford University and Dr. Gregg L. Semenza of Johns Hopkins University School of Medicine. The prize was awarded for their work on discovering how cells detect and respond to changes in oxygen availability, a process that is key to the survival of many cancers.
Dr. Kaelin is a professor in the Department of Medicine at the Dana Farber Cancer Institute at Harvard Medical School and a Howard Hughes Medical Institute investigator. Dr. Kaelin is also an advisor to Circle Pharma.
In separate work, Dr. Kaelin and his colleagues at Dana Farber Cancer Institute identified cyclins A and E as potential targets for disrupting the growth of certain cancers. Their studies with peptide tool compounds showed that inhibiting these targets can selectively kill cancers that are dysregulated in the Rb pathway, in a process known as synthetic lethality. With guidance from Dr. Kaelin, Circle is developing macrocycles that inhibit cyclins A and E as potential new cancer therapies.
“We are thrilled that the pioneering work of Drs. Kaelin, Ratcliffe and Semenza has been recognized with the award of the Nobel Prize and congratulate them on this well-deserved recognition,” said Dr. David J. Earp, Circle’s CEO.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. 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. Its lead program targets cyclins A and E, which are part of the regulatory machinery that controls the progression of cells through the cell growth and division cycle. Inhibiting cyclins A and E has been shown to be synthetic lethal in cancers that carry mutations causing dysregulation of the Rb pathway.
Contacts
David J. Earp, JD, PhD., 650.392.0350
info@circlepharma.com
by Richard Stein, M.D., Ph.D.
April 01, 2018
Advantages May Place Peptides Ahead of Small-Molecule Drugs
Peptide therapeutics would seem to occupy a sweet spot between small molecules and biologics. Small molecules, which represent the majority of clinical drugs, preferentially bind hydrophobic pockets or cavities, but targeting them to protein interfaces that are large or shallow, or contain combinations of polar and apolar residues, is challenging.
Biologics, or larger molecules, use more extensive contact areas and can modulate protein–protein interactions extracellularly, but are difficult to deliver into cells.
The difficulties posed by small molecules and biologics could be avoided by peptide therapeutics, which present drug developers with distinct advantages. These include simpler production, lower costs, and superior safety and tolerability. Consequently, some drug developers see peptide therapeutics as an attractive means of reaching targets that are known to be therapeutically relevant but are, as yet, “undruggable.” Peptide therapeutics, however, need to manifest sweet spots of their own.
Read complete article here or at Genengnews
By Michael Fitzhugh
Staff Writer
Circle Pharma Inc., of South San Francisco, said its first collaboration with Pfizer Inc. has led to the identification of a series of bioavailable macrocyclic peptides capable of acting as potent and cell-permeable modulators of CXCR7…
Read article at BioWorld
SOUTH SAN FRANCISCO, Calif.- (BUSINESS WIRE) -Circle Pharma, Inc. today announced that results from its collaborative work with Pfizer Inc. to develop a potent and orally bioavailable macrocycle modulator of the chemokine receptor, CXCR7, have been published in the Journal of Medicinal Chemistry.
The goal of the collaboration was to deploy Circle’s rational design platform for macrocycle therapeutics in order to improve the drug-like characteristics of an existing macrocycle compound, and in particular to develop a cell permeable, orally bioavailable compound with enhanced target affinity. As reported in the publication, the collaboration produced a series of permeable and potent derivative macrocycles, including a compound having >500-fold increase in potency (CXCR7 Ki of ~ 9nM versus 2 uM for the starting compound), good cell permeability and 18% oral bioavailability in rats.
Additionally, permeable CXCR7 binding compounds with novel macrocycle backbone scaffolds were discovered through the efforts of the collaboration. This finding was not described in the publication.
“Cell permeability and orally bioavailability have been long-standing and well recognized challenges in the development of macrocycle therapeutics: nearly all synthetic macrocycle compounds in clinical development are against extracellular targets and are delivered by injection,” noted David J. Earp, JD, PhD, Circle’s CEO. “Circle’s rational design approach coupled with efficient, low-cost synthesis uniquely enables us to design cell permeable, bioavailable macrocycles to address therapeutic targets that have been out of reach, including intracellular protein-protein interactions. This is a large target class with significant unmet clinical need.”
“This collaboration successfully achieved its very challenging objective of delivering a potent and orally bioavailable macrocycle targeting CXCR7,” said Spiros Liras, PhD, Vice President, Medicinal Chemistry, Pfizer.
The open-access scientific paper, entitled “Discovery of Potent and Orally Bioavailable Macrocyclic Peptide–Peptoid Hybrid CXCR7 Modulators,” is available at http://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01028.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to allow drug developers to address the large proportion of known 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 by the need for a greater understanding of how to develop macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Circle is applying its ability to design potent macrocycles with intrinsic cell permeability and drug-like characteristics to unlock access to challenging, high value therapeutic targets that have been out of reach by other approaches.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. 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. Circle’s founders are Prof. Matthew P. Jacobson (Chair of the Dept. of Pharmaceutical Chemistry at UC San Francisco and co-founder of Global Blood Therapeutics (NASDAQ: GBT) and Relay Therapeutics) and Prof. R. Scott Lokey (Dept. of Chemistry and Biochemistry, UC Santa Cruz and director of the UCSC Chemical Screening Center).
More information: www.circlepharma.com
Circle Pharma, Inc.
Cayla McEwen, 650-392-0363
info@circlepharma.com
Read online article
SOUTH SAN FRANCISCO, Calif. – (BUSINESS WIRE) – Circle Pharma, Inc., a developer of macrocycle therapeutics, today announced that David Spellmeyer, PhD, has been appointed as its chief scientific officer.
“His deep experience in rational drug design and discovery is an excellent fit for Circle as we extend our platform for macrocycle discovery and advance our therapeutic pipeline towards the clinic.”
Dr. Spellmeyer brings over 25 years of broad industrial experience to Circle. He previously served as CTO & CIO at Nodality, CSO at Signature BioScience, Research Staff Member at IBM, as well as scientific, quality systems, and leadership roles at other biotechnology companies. David has been involved in more than 20 strategic corporate partnerships, M&A, and joint ventures, as well as several rounds of venture financing.
“We are delighted to welcome David to Circle’s senior leadership,” said David J. Earp, JD, PhD, Circle’s CEO. “His deep experience in rational drug design and discovery is an excellent fit for Circle as we extend our platform for macrocycle discovery and advance our therapeutic pipeline towards the clinic.”
“Circle is at an exciting point in its development. I am thrilled to be joining a company that has built such a promising discovery platform,” said Dr. Spellmeyer. “The combination of rational design and efficient, automated macrocycle synthesis is a new approach to this drug class, and the results so far are highly encouraging.”
Dr. Spellmeyer received his PhD in 1987 from UCLA, and completed his post-doctoral work in pharmaceutical chemistry at UCSF, where he holds an appointment as an adjunct associate professor in the Department of Pharmaceutical Chemistry. David was named as a Fellow of the American Chemical Society in 2009. He joins Circle’s team after working with the company in his role as an Executive-in-Residence at ShangPharma Innovation, an investor in Circle. He continues to advise ShangPharma in an EIR capacity.
About Macrocyclic Peptides
Macrocyclic peptides have the potential to allow drug developers to address the large proportion of known 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 by the need for a greater understanding of how to develop macrocycles with appropriate pharmacokinetics, cell permeability and oral bioavailability. Circle is applying its ability to design potent macrocycles with intrinsic cell permeability and drug-like characteristics to unlock access to challenging, high value therapeutic targets that have been out of reach to other approaches.
About Circle Pharma, Inc.
Circle is developing a new paradigm for macrocycle drug discovery based on rational design and synthetic chemistry. 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. Circle’s founders are Prof. Matthew P. Jacobson (Chair of the Dept. of Pharmaceutical Chemistry at UC San Francisco and co-founder of Global Blood Therapeutics (NASDAQ: GBT) and Relay Therapeutics) and Prof. R. Scott Lokey (Dept. of Chemistry and Biochemistry, UC Santa Cruz and director of the UCSC Chemical Screening Center).
More information: www.circlepharma.com
Contacts
Circle Pharma, Inc.
Cayla McEwen, 650-392-0363
info@circlepharma.com
Read online article
Introduction
Cyclic peptide natural products and their synthetic mimics have gained prominence as potential sources of next‐generation therapeutics and biological probes [1–4]. The size and structural complexity of these compounds sets them apart from common synthetic drugs, allowing them to access the “undruggable” target space beyond enzymatic active sites and receptor binding pockets to include activities against a variety of nontraditional targets [4]. Although cyclic peptides have molecular weights and polar group counts that exceed the typical parameters for “drug‐likeness” [5, 6], many are capable of penetrating cells by passive diffusion, and some, such as cyclosporin A, are orally bioavailable [7]. Passive diffusion offers an advantage over other forms of permeation such as paracellular transport, carrier‐mediated transport, and active non‐receptor‐mediated uptake (e.g., micropinocytosis) because the ability to cross the membrane is dictated by the intrinsic properties of the molecule (e.g., molecular weight, number of intramolecular hydrogen bonds (IMHBs), polar surface area, flexibility, lipophilicity) rather than those of the target tissue or cellular physiology (e.g., size of tight junctions, type of transport proteins, invagination of the membrane in response to surface assemblies). Thus, these natural products may provide insights into the requirements for optimizing the ADME properties of large macrocycles.
Further, the stereochemical and conformational complexity of cyclic peptides serves as a model for the design of synthetic scaffolds capable of modulating challenging biological targets such as protein–protein interactions and allosteric binding sites in both extracellular and intracellular space [8–13]. Despite this potential, few efforts have been made to systematically assess the relationship between the structure, pharmacokinetics, and bioactivity of cyclic peptide natural products. This is due in part to the limited number of known passively permeable cyclic peptide and cyclic peptide/polyketide natural products. Therefore the generality of cyclic peptides as orally bioavailable bioactive scaffolds remains an open question.
The few studies that have systematically explored the relationships between structure and permeability in cyclic peptides have been limited to a small subset of methylated (1) [14] and non‐methylated (2) [15] cyclic hexapeptide scaffolds that bear resemblance to baceridin (3) [16], segelin I (4) [17], and the nocardiamide (5/6) [18] cyclic hexapeptide natural products (Figure 5.1 and Chapter 3) [19–22].
The work of Lokey and Jacobson [23–27], Fairlie and Craik [28–30], and others has begun to elucidate the structure– permeability relationships of more complex natural products, but the vast majority of these studies have been limited to cyclic penta‐ and hexapeptides with no observed bioactivity. Thus, the new frontier in understanding structure–permeability relationships in cyclic peptides has moved to the chemical space that encompasses macrocycles of higher molecular weight [31, 32], greater structural complexity, and significant bioactivity.
Here, we first discuss the two‐dimensional and three dimensional (3D) structures of known passively permeable cyclic peptide natural products and then highlight recently discovered cyclic peptide natural products with notable bioactivity that could serve as starting structures for future systematic structural studies to optimize oral absorption.
October 2017
Wiley Publishers
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by Markus Boehm, Kevin Beaumont, Rhys M Jones, Amit S. Kalgutkar, Liying Zhang, Karen Atkinson, Guoyun Bai, Janice A. Brown, Heather Eng, Gilles H. Goetz, Brian R Holder, Bhagyashree Khunte, Sarah Lazzaro, Chris Limberakis, Sangwoo Ryu, Michael J Shapiro, Laurie Tylaska, Jiangli Yan, Rushia Turner, Siegfried S. F. Leung, Mahesh Ramaseshan, David A. Price, Spiros Liras, Matthew P Jacobson, David J. Earp, R. Scott Lokey, Alan M Mathiowetz, and Elnaz Menhaji-Klotz
Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators.
ABSTRACT: The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side chain diversity well beyond that of natural amino acids. At the same time, computational calculations and experimental assays were used to track and reduce polarity while closely monitoring physicochemical properties. This strategy led to the discovery of macrocyclic peptide-peptoid hybrids with high CXCR7 binding affinities (Ki < 100 nM) and measurable passive permeability (Papp > 5 x 10-6 cm/sec). Moreover, bioactive peptide 25 (Ki = 9 nM) achieved oral bioavailability of 18% in rats, which was commensurate with the observed plasma clearance values upon intravenous administration.
October 18, 2017
Journal of Medicinal Chemistry
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by Matthew R. Naylor, Andrew T. Bockus, Maria-Jesus Blanco, Scott Lokey
Highlights
As interest in protein–protein interactions and other previously-undruggable targets increases, medicinal chemists are returning to natural products for design inspiration toward molecules that transcend the paradigm of small molecule drugs. These compounds, especially peptides, often have poor ADME properties and thus require a more nuanced understanding of structure-property relationships to achieve desirable oral bioavailability. Although there have been few clinical successes in this chemical space to date, recent work has identified opportunities to introduce favorable physicochemical properties to peptidic macrocycles that maintain activity and oral bioavailability.
May 29, 2017
Elsevier
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