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Encycle Therapeutics and University of Toronto | Date: 2017-09-27

The present invention relates to cyclic amino acid molecules and methods of preparing the same, and in particular the macrocyclization of amino acids or linear peptides bound to a solid support.


Zaretsky S.,University of Toronto | Hickey J.L.,Encycle Therapeutics | St. Denis M.A.,Encycle Therapeutics | Scully C.C.G.,University of Toronto | And 4 more authors.
Tetrahedron | Year: 2014

A hybrid sequential molecular mechanics and quantum mechanical approach to modeling cyclic peptides has led to an effective method for predicting their 1H and 13C NMR chemical shift values. The method was first developed to predict chemical shifts in chloroform before being adapted to a more peptide friendly solvent, DMSO. Finally the effectiveness of this method was tested in a blind fashion and excellent agreement with the experimental NMR chemical shifts was observed. © 2014 Elsevier Ltd. All rights reserved.


TORONTO, ON--(Marketwired - November 21, 2016) - Toronto-based MaRS Innovation announced today that one of its leading portfolio companies, Triphase Accelerator Corporation (Triphase), has agreed to sell assets relating to its first investigational compound, marizomib (MRZ) to U.S.-based Celgene Corporation, through an affiliate, for an undisclosed amount. Marizomib is the first major divestiture of a compound developed inside a MaRS Innovation portfolio company. Triphase was established by MaRS Innovation in partnership with the Ontario Institute for Cancer Research (OICR) and MaRS Discovery District, with a single powerful mandate of seeking out oncology innovations with the potential to lead to patient therapies that could be quickly taken into clinical development. As part of this mandate, the clinical asset marizomib (MRZ), a novel brain-penetrant proteasome inhibitor, was identified that showed promise in the fight against glioblastoma -- a common and aggressive malignant brain tumour. Marizomib is currently in development for patients with glioblastoma and relapsed and/or refractory multiple myeloma. Glioblastoma occurs in two to three per 100,000 people in Canada, the United States and Europe and accounts for about 15 per cent of all primary brain tumours. It is most commonly found in older individuals and more prevalent in men than women. Marizomib is currently being evaluated in clinical studies in combination with bevacizumab (Avastin®) and as monotherapy in patients with glioblastoma. As part of its mission, MaRS Innovation was instrumental in building the leadership team inside Triphase, providing seed funding as well as facilitating discussions with external investors. After two years of development, Celgene was introduced to Triphase. "This engagement between Celgene and Triphase reinforces MaRS Innovation's commitment to Triphase as a company dedicated to advancing novel compounds through Phase 2 proof-of-concept clinical studies," said Dr. Rafi Hofstein, President and CEO, MaRS Innovation. "Companies like Celgene recognize the importance of pursuing avenues of medical innovation to advance the science more quickly and address unmet needs." The Celgene deal marks the first major exit for MaRS Innovation. MaRS Innovation plans on reinvesting the proceeds from this and future transactions back into its portfolio of companies, fostering new opportunities and setting itself on a path of becoming a self-sustaining centre of innovation. "We plan on reinvesting back into the companies we have in our portfolio," commented Dr. Hofstein. "This will accelerate the development of cutting-edge science and emerging technologies. This is not only good for our portfolio but it's also good for our 15 Member Institutions and for the greater Canadian innovation community." Triphase is one example of the many portfolio companies MaRS Innovation has in its pipeline. MaRS Innovation continues to advance its 60 plus companies in areas as diverse as therapeutics, medical devices, clean technology and information technology. Encycle Therapeutics, a spin-off from the University of Toronto is developing novel enhanced cyclic peptides, which are being developed for treatment of inflammatory bowel disease (among other inflammatory diseases) as well as novel cyclic peptide-based treatment for a variety of cancer diseases. XOR Labs, a spin-off from University Health Network is changing the face of organ transplantation by exponentially increasing the number of donated lungs available for transplantation around the world. ScarX Therapeutics, a spin-off from SickKids Hospital is a biotechnology company that discovers and develops innovative treatments for dermal scarring (fibrosis). ScarX's lead candidate, SCX-001, shows promise as the first prescription cream for the reduction of post-surgical scarring. Flybits, a Ryerson spin-off is the world's only context-as-a-service product providing instant cloud access to everything needed to transform the mobile experience from generic and static to personalized and dynamic. The technology offers a unique approach to understanding where the user is currently located. About MaRS Innovation MaRS Innovation is the commercialization agent for 15 of Ontario's leading academic institutions. It provides investors and licensees access to technology assets emerging from MaRS Innovation's members, who receive over a billion dollars in annual research and development funding. Supported by the Government of Canada through the Networks of Centres of Excellence, by the Government of Ontario through the Ontario Centres of Excellence, Ministry of Research, Innovation and Science, and by its members, MaRS Innovation is a transformational partnership that turns research strengths into commercial opportunities through industry partnerships, licensing and company creation. About Triphase Accelerator Corporation Triphase Accelerator Corporation is a private drug development company with a primary focus on oncology and with operations in Toronto, ON and San Diego, CA. Triphase Accelerator Corporation is dedicated to advancing novel compounds through Phase 2 proof-of-concept clinical studies using a unique, science-based, high-quality model that is faster and more cost-effective than traditional pharmaceutical and biotech industry drug development approaches. Triphase Accelerator Corporation was spun out of the Ontario Institute for Cancer Research (OICR), with support from the Fight Against Cancer Innovation Trust (FACIT), MaRS Innovation and MaRS Discovery District. It has a strategic relationship with Celgene for marizomib. Website: www.triphaseco.com


Zaretsky S.,University of Toronto | Adachi S.,University of Toronto | Rotstein B.H.,University of Toronto | Hickey J.L.,Encycle Therapeutics | And 6 more authors.
Journal of Organic Chemistry | Year: 2014

The factors determining diastereoselectivity observed in the multicomponent conversion of amino acids, aziridine aldehyde dimers, and isocyanides into chiral piperazinones have been investigated. Amino acid-dependent selectivity for either trans- or cis-substituted piperazinone products has been achieved. An experimentally determined diastereoselectivity model for the three-component reaction driven by aziridine aldehyde dimers has predictive value for different substrate classes. Moreover, this model is useful in reconciling the previously reported observations in multicomponent reactions between isocyanides, α-amino acids, and monofunctional aldehydes. © 2014 American Chemical Society.


Zaretsky S.,University of Toronto | Hickey J.L.,University of Toronto | Hickey J.L.,Encycle Therapeutics | Tan J.,University of Toronto | And 7 more authors.
Chemical Science | Year: 2015

Aziridine aldehyde dimers, peptides, and isocyanides participate in a multicomponent reaction to yield peptide macrocycles. We have investigated the selectivity and kinetics of this process and performed a detailed analysis of its chemoselectivity. While the reactants encompass all of the elements of the traditional Ugi four-component condensation, there is a significant deviation from the previously proposed mechanism. Our results provide evidence for an imidoanhydride pathway in peptide macrocyclization and lend justification for the diastereoselectivity and high effective molarity observed in the reaction. © 2015 Royal Society of Chemistry.


Zaretsky S.,University of Toronto | Hickey J.L.,University of Toronto | Hickey J.L.,Encycle Therapeutics | Tan J.,University of Toronto | And 5 more authors.
Chemical Science | Year: 2015

Aziridine aldehyde dimers, peptides, and isocyanides participate in a multicomponent reaction to yield peptide macrocycles. We have investigated the selectivity and kinetics of this process and performed a detailed analysis of its chemoselectivity. While the reactants encompass all of the elements of the traditional Ugi four-component condensation, there is a significant deviation from the previously proposed mechanism. Our results provide evidence for an imidoanhydride pathway in peptide macrocyclization and lend justification for the diastereoselectivity and high effective molarity observed in the reaction. © 2015 Royal Society of Chemistry.


Low K.E.,Queen's University | Ler S.,University of Toronto | Chen K.J.,Queen's University | Campbell R.L.,Queen's University | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2016

Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a β-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor. © 2016 American Chemical Society.


PubMed | University of Toronto and Encycle Therapeutics
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.


PubMed | University of Toronto, Encycle Therapeutics and Queen's University
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016

Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by natures hint that a -turn loop within calpastatin forms a broad interaction around calpains active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor.

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