The Coferon technology platform is anchored around proprietary reversible, covalent summa linker chemistry. Although the dimeric form constitutes the active moiety in terms of therapeutic activity and also comprises the Active Pharmaceutical Ingredient (API) optimized for oral delivery, it is the re-deployable summa linker chemistry that imparts the truly unique and differentiating aspects of the Coferon Platform. Designed to dissociate under physiological conditions, the monomers are optimized in the pre-clinical drug discovery/early development stage to be absorbed and distributed to the target tissue. Upon entering target cells these low molecular weight (typically 400-600 Daltons) monomers are driven to bind their intracellular molecular target by a modest affinity pharmacophore, whereupon they covalently dimerize to form a significantly higher affinity and more specific large molecule which we have shown can possess extraordinarily slow dissociation off-rates from the bound protein target after optimization.
In designing these molecules, a small “summa linker” moiety coupled through an appropriate “connector” to provide the ideal spatial orientation for the target - is appended to the pharmacophore to enable rapid, reversible, bioorthogonal, covalent dimerization. Homo- and hetero-dimeric summa linker chemistries have been developed and validated against human mast cell ß-tryptase (a tetrameric protease).
The powerful combinatorial screening potential of heterodimerizing coferons allows the rapid exploration of a large number of permutations of pharmacophores, orientations and structure-activity relationships, thereby accelerating the drug discovery process. Once potent combinations are identified by their tight-binding properties we apply medicinal chemistry principles to optimize potency, permeability, metabolic stability, and pharmacokinetics to improve delivery in vivo. In addition, once the optimal distance and disposition of the pharmacophores is established, alternate linker chemistries may be introduced to improve oral bioavailability and to increase target residence time, maximizing in vivo efficacy and potency. We believe that the Coferon technology platform provides an opportunity to radically accelerate the drug discovery process and improve the delivery of therapeutic agents targeting protein-protein interactions. The technology is particularly well suited for specific targeting of epigenetic regulatory elements as well as providing a vehicle for resolving issues in more traditional target programs where classic small molecule approaches have reached an impasse.
The human ß-tryptase proof-of-concept project has been able to demonstrate the validity of the coferon concept by showing effective dimerization and inhibition of ß-tryptase in cell free systems (where multiple homo- and heterodimeric coferon pairs have been confirmed to bind ß-tryptase in the predicted manner using X-ray crystallography); in cellular assays; and, in an in vivo model that demonstrated the ability to inhibit ß-tryptase activity in a subcutaneously implanted human mast cell tumor after parenteral and oral administration to nude mice. In addition, we have been able to mitigate major concerns regarding the effects of the summa linker moieties, with respect to absorption, distribution, metabolism, excretion, and toleration (ADMET) properties, with numerous coferons displaying impressive in vitro metabolic stabilities, minimal potency shifts in plasma, good in vivo pharmacokinetic behavior, and high oral bioavailability with no evidence of toxicities.
We have supported the core platform science by filing a broadly encompassing IP estate around the evolving chemistry and the ideas and concepts for its application. Currently, beyond the original two patent filings there are a dozen additional patent filings relating to the Coferon technology and inventions.
We are now conducting drug discovery projects in the areas of epigenetics and against selected targets (initially in anti-infectives) where we believe the platform can be used to resolve challenges in drug development and clinical utility that have been encountered by classic small molecule approaches.
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