Circle Pharma, Inc. today announced that it has completed an expansion of its Series A financing, with new investors W.I. Harper Group, Elements Partners, LLC, Whitesun Healthcare Ventures Limited and LifeForce Capital joining the round. Mission Bay Capital led Circle’s Series A, with Pfizer Inc. (NYSE:PFE), ShangPharma Investment Group, Ltd. and a syndicated group of individual investors subscribing at the initial close. With this subsequent closing, a total of approximately $6.5M of shares of Circle’s Series A Preferred Stock has been issued in the Series A financing.
“We are gratified to have this new group of high-caliber investors joining our first equity financing,” said David J. Earp, J.D., Ph.D., Circle’s president and CEO. “The funds will support Circle’s platform development and our therapeutic pipeline, which is focused on intracellular protein-protein interactions that are key drivers in oncogenic pathways. This is an exciting time for Circle. We are adding new targets to our pipeline, including MCL1 and the substrate binding site of cyclinA / cdk2, both of which are important oncology targets that have proven challenging for small molecule drug development. Our chemistry process development work has recently successfully achieved key steps required for a more highly automated synthesis platform. Finally, with support from Pfizer, we are building a physical library of macrocycles which are predicted to have optimized permeability. This library will complement our rational design/virtual library screening approach. We will begin synthesis of the physical library shortly, enabling us to deliver it to Pfizer, and potentially other collaborators, for screening use later this year. We are especially delighted to welcome James Lu to our board in connection with this expanded Series A investment. He brings deep experience building high-growth, global companies both as an investor and in management roles.”
Mr. Lu is a Managing Director of WI Harper, a cross border venture capital firm investing in leading healthcare and technology startups in the U.S. and China. Previously, Mr. Lu co-founded and was a General Partner of iD Ventures America (formerly Acer Technology Ventures), which managed several funds that were early investors in companies such as iRobot (NASDAQ:IRBT); Harmonix Music (acquired by MTV/Viacom (NYSE:VIA)); and Monolithic Power Systems (NASDAQ:MPWR). In prior roles, Mr. Lu was General Counsel of the Acer Group and earlier was a corporate and commercial attorney with the McCutchen law firm in San Francisco and a banker at JP Morgan in New York. Mr. Lu graduated with a BA from Yale College, an MBA from Harvard Business School and a JD from UC Berkeley School of Law.
Peter Liu, Founder and Chairman of WI Harper Group commented “we are seeing excellent opportunities for investing in ground-breaking life science companies that are advancing new technologies and addressing unsolved problems. Circle Pharma is one such company; we are pleased to participate in their Series A financing and look forward to building a strong relationship with the management team and the other investors.”
“Completion of Circle’s Series A financing strengthens Circle’s investor base and brings additional depth on the technical side, relations with strategic partners and, with WI Harper and Elements, connections to activities and initiatives outside of the U.S., and especially in key Asia markets,” said Douglas Crawford, Ph.D., managing director of Mission Bay Capital.
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).
South San Francisco, CA, April 25, 2017
by Cameron R. Pye, William M. Hewitt, Joshua Schwochert, Terra D. Haddad, Chad E. Townsend, Lyns Etienne, Yongtong Lao, Chris Limberakis, Akihiro Furukawa, Alan M. Mathiowetz, David A. Price, Spiros Liras, and R. Scott Lokey
Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (∼800 Da < MW < ∼1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation…
January 6, 2017
Journal of Medicinal Chemistry
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Circle Pharma, Inc. today announced a Series A financing round in which it has issued over $4.5M of shares of Series A Preferred Stock. The financing was led by Mission Bay Capital, with Pfizer Inc. (NYSE:PFE), ShangPharma Investment Group, Ltd. and a syndicated group of individual investors joining the round. In connection with the financing, Walter H. Moos, Ph.D., representing ShangPharma, has joined the Circle Board of Directors.
“We are delighted with the participation of such high caliber investors in our first equity round,” said David J. Earp, J.D., Ph.D., Circle’s president and CEO. “With our seed funding, we established Circle’s computational design platform, advanced our synthetic chemistry capabilities in collaboration with ChemPartner, and engaged in a target-based collaboration with Pfizer. The Series A funds will be used to support Circle’s therapeutic pipeline, which is focused on intracellular protein-protein interactions that are key drivers in oncogenic pathways. We are also now building a physical library of cell- permeable macrocycles to augment our computational design tools, and this library will later be available to our collaboration partners. We are particularly excited to welcome Walter Moos to our Board of Directors. Dr. Moos brings a wealth of life sciences R&D experience, having served most recently as the president of SRI Biosciences and previously in senior executive roles at MitoKor, Chiron and Warner-Lambert/Parke-Davis. His teams have advanced numerous pharmaceutical products from discovery to commercialization, and we are fortunate to have him join Circle.”
“I am very much looking forward to taking an active role on Circle’s board,” said Walter Moos. “The combination of innovative technology and the great team at Circle could help unlock high value targets that have long been considered out of reach of drug developers.”
Dr. Moos has served on about 20 business and scientific boards, including Amunix, Oncologic (Aduro), Onyx (Amgen), Rigel and the Biotechnology Industry Organization (BIO).
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’s ability to design potent macrocycles with intrinsic cell permeability could 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).
December 21, 2016, South San Francisco
by Akihiro Furukawa, Chad E. Townsend, Joshua Schwochert, Cameron R. Pye, Maria A. Bednarek, and R. Scott Lokey
Synthetic and natural cyclic peptides provide a testing ground for studying membrane permeability in nontraditional drug scaffolds. Cyclic peptomers, which incorporate peptide and N-alkylglycine (peptoid) residues, combine the stereochemical and geometric complexity of peptides with the functional group diversity accessible to peptoids. We synthesized cyclic peptomer libraries by split-pool techniques, separately permuting side chain and backbone geometry, and analyzed their membrane permeabilities using the parallel artificial membrane permeability assay. Nearly half of the side chain permutations had permeability coefficients (Papp) > 1 × 10–6 cm/s. Some backbone geometries enhanced permeability due to their ability to form more stable intramolecular hydrogen bond networks compared with other scaffolds. These observations suggest that hexameric cyclic peptomers can have good passive permeability even in the context of extensive side chain and backbone variation, and that high permeability can generally be achieved within a relatively wide lipophilicity range.
October 3, 2016
Journal of Medicinal Chemistry
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CirclePharma, Inc., today announced that it will apply its computational design and synthetic chemistry platform to design and create a physical screening library of novel macrocyclicpeptides. Once completed, the library is initially expected to comprise several hundred macrocycles that will be designed to potentially disrupt bioactive conformations commonly found in protein-protein interactions known to drive disease processes, and will deploy backbone scaffolds screened in silica for intrinsic cell permeability characteristics. In addition, the design of the library will permit the simple creation of derivative libraries tailored to specific features of a therapeutic target class.
PfizerInc.(NYSE:PFE) has entered into an agreement with Circle under which Pfizer will provide support for the library build, and Circle has granted Pfizer non-exclusive rights to screen the library against certaintargets. The rights granted to Pfizer exclude specified targets for which Circle has reserved exclusive rights to screen the library.
“This physical library will complement Circle’s target-specific computational design toolkit,” said David J. Earp, J.D., Ph.D., Circle’s President and CEO. “We expect to use the library for our internal pipeline discovery work, and we will make it available to all of our collaboration partners in drug discovery.”
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. Inparticular, 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 pharm acokinetics, cell permeability and oral bioavailability. As a result, most clinical-stage macro cyclic 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), 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.
September 12, 2016, South San Francisco, CA
by Joshua Schwochert, Yongtong Lao, Cameron R. Pye, Matthew R. Naylor, Prashant V. Desai, Isabel C. Gonzalez Valcarcel, Jaclyn A. Barrett, Geri Sawada, Maria-Jesus Blanco, and R. Scott Lokey
Cyclic peptide (CP) natural products provide useful model systems for mapping “beyond-Rule-of-5” (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.
June 6, 2016
ACS Medicinal Chemistry Letter
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by Leung SS, Sindhikara D, Jacobson MP
We investigate the relationship between passive permeability and molecular size, in the context of solubility-diffusion theory, using a diverse compound set with molecular weights ranging from 151 to 828, which have all been characterized in a consistent manner using the RRCK cell monolayer assay. Computationally, each compound was subjected to extensive conformational search and physics-based permeability prediction, and multiple linear regression analyses were subsequently performed to determine, empirically, the relative contributions of hydrophobicity and molecular size to passive permeation in the RRCK assay. Additional analyses of Log D and PAMPA data suggest that these measurements are not size selective, a possible reason for their sometimes weak correlation with cell-based permeability.
May 23, 2016
Journal of Chemical Information and Modeling
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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
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