Our end-to-end differentiated capabilities to prosecute targets across therapeutic areas via heterobifunctionals rest on four cornerstones, which we are applying beyond degraders:
Degradability Demonstration and E3 Ligase Fitness
We are utilizing our Biodegrader platform to elucidate the degradability of a protein or the fitness of an E3 ligase, in cases where a ligand for the POI or E3 ligase may not exist. These cell systems interrogate the ability of a protein-reporter fusion to degrade the protein of interest. Excitingly, our approach allows the screening of multiple E3 ligases, thus inferring which one is the most suited for a given protein of interest.
New Proprietary Ligands
We are combining integrated hit finding screening technologies with proprietary compound collections to identify high quality proprietary ligands for both the protein of interest and novel, and in some cases tissue selective, E3 ligases. This covers virtual-ligand screening (VLS) leveraging our computational platform, high throughput screening (HTS), DNA-encoded libraries (DEL), fragment and covalent and knowledge base libraries. In addition, our physics-based platform, combined with our integrated experimental capabilities serves to accelerate hit and lead optimization approaches.
Predictive Heterobifunctional Assembly
- formation of the ternary complex induced by a degrader molecule
- conformational heterogeneity of the ternary complex,
- degradation efficiency via the ubiquitin ligase macromolecular assembly
Achieving oral bioavailability for non-cereblon recruited heterobifunctional degraders remains a significant challenge. In order to systematically enable oral delivery beyond cereblon ligands, we are driving our molecular design: by integrating in silico assays focusing on the identification of low clearance, good solubility, maximum permeability, and high catalytic protein turnover early in our design process. Thoughtful and disciplined design maximizes the probability of our heterobifunctional degraders being amenable to oral absorption. Oral delivery is then further enabled through advanced formulation and delivery, for which we are investing in the development of formulation and delivery techniques intended to increase bioavailability.
Atomic-Resolution Prediction of TPD Complex Structures by Combining MD with Experimental HDX-MS
We develop Covalent Therapeutics using our proprietary suite of proteome-wide datasets, assays, and covalent library.
Designing Best-in-Class Small Molecules
Our computation-first approach is used to design molecules that rapidly reach the desired TPP for disease areas where effective therapeutic solutions are lacking.