C4 Therapeutics has pioneered a new and quantitative approach to the discovery of degrader molecules that can target proteins that cause serious disease.
The C4T TORPEDO™ platform (Target ORiented ProtEin Degrader Optimizer) is an integrated approach that uses proprietary assays and quantitative data to accelerate drug design. The concepts underpinning our approach have been published (Fisher and Phillips, Curr. Opin. Chem. Biol. 2018, 44: 47-55).
Since C4T was founded in 2016 we have accumulated comprehensive data for hundreds of high quality degrader molecules directed to degrading a number of target proteins. We leverage this data in combination with leading expertise in the structural biology of E3 ligases and sophisticated computational models to understand the interactions between the target protein, E3 ligase, and degrader molecule. This knowledge fuels the C4T TORPEDO™ platform chemistry engine and enables us to optimize the specificity and potency of degrader molecules.
Understanding Degrader Function
Degraders act unlike most available drugs and understanding their function requires new assays and approaches that we have pioneered. Our approach involves two key elements: (i) predicting and measuring key components of interactions between the protein, the degrader molecule, and the ubiquitination machinery and (ii) understanding the rate of ubiquitination of the target protein and its subsequent degradation. In 2016, we innovated the use of Promega’s HiBit assay system to produce the high quality data needed to fully understand the relationship between degrader function and the features needed for maximally effective degrader drugs. Today we integrate this data into predictive models that allow us to predict key features and rapidly optimize the the specificity and potency of degrader molecules.
understanding degrader effects in disease relevant models
Degraders optimized using the C4T TORPEDO™ platform approach allow for rapid testing in vivo to evaluate disease-relevant effects and inform further optimization of degradation and drug properties. As shown in the figure below, exemplary degraders can result in significant therapeutic effects in mouse xenograft models of human cancers. In this case, there is a notable difference between the effect observed with inhibitors and the effect observed with a degrader.