Reversible Covalent Technology

Principia Biopharma was founded to commercialize important drug design discoveries made by Jack Taunton Ph.D., a Howard Hughes Medical Investigator at UCSF.  Dr. Taunton's technology, enabled by significant advancements and intellectual property developed at Principia, permits a highly specific and durable, yet reversible, covalent bond between a compound and specific amino acids within the target site.

Background

While Principia’s discovery platform can address many different target classes, our initial focus has been on kinases.  Traditionally, kinase inhibition discovery efforts have focused on either irreversible inhibitors or reversible non-covalent inhibitors.  Both of these approaches have limitations. 

Reversible covalent technology combines the best aspects of both irreversible and reversible non-covalent target inhibition. The covalent bond formed by our technology is further stabilized by additional specific, but weaker scaffold interactions. The covalent bond is durable, but only in the presence of these weaker scaffold interactions.  When the weaker bonds break, the covalent bond breaks as well, and the target is no longer bound.  Thus reversible covalent target inhibition combines the long duration of action of irreversible inhibition with the selectivity and reversibility of reversible non-covalent inhibition. 

The Platform

Principia’s discovery and development platform comprises a collection of capabilities to expedite the drug discovery and development process.  Our suite of tools contains proprietary methods to model reversible covalent interactions, an in-house library of chemistries, and the knowledge of how these chemistries interact with targets.  In addition, Principia has developed customized assays, including biochemical, cellular and pharmacodynamic assays.  Knowledge gained from these assays allows Principia to optimize residency time and uncouple pharmacodynamics from pharmacokinetics.  With Principia’s platform approach, the durability of target inhibition is no longer just a function of drug exposure, but a tunable feature which can be optimized early in the discovery process.

Benefits of the Platform

1. Superior Product Attributes

Principia’s proprietary reversible covalent technology produces compounds with superior profiles:

  Irreversible Reversible
Non-covalent		 Reversible
Covalent
High potency
High selectivity    
Long duration of action  
Reversibility  
Potential for chronic dosing  
  • Potency:  Principia compounds are very potent, and can bind their target rapidly at low nanomolar to picomolar range.
  • Selectivity:  For compounds created with Principia’s platform, even slight changes in the binding pocket result in low affinity and transient interactions between the compound and off-targets.  The native protein is not modified permanently, and when the protein denatures, the bonds break and the compound is released.  The unmodified protein can then be degraded through normal cellular processes.  Since the drug is no longer attached to the denatured protein, there are no adducts to be recognized by the immune system as immunogenic.  This feature may be especially relevant when addressing chronic diseases, including autoimmune disease and inflammation.
  • Durability:  Principia’s proprietary platform can create drugs optimized to occupy the target for a specific length of time.  In work completed so far, Principia compounds have shown a range of cellular occupancy times from minutes to 24 hours.
2. Acceleration of the Drug Discovery Process

Principia can efficiently optimize compounds that bind weakly into drug candidates that have low or sub nanomolar potency and a high degree of selectivity. The path to mature clinical development candidates can therefore be accelerated. 

3. Broad Applicability

Principia’s technology is applicable across many target classes and therapeutic areas.  The technology can also reach targets currently not addressable by traditional discovery methods.