Molecular Degraders of Extracellular Proteins

Yale University, New Haven CT

Investigators

Abstract

Abstract The majority of small molecule therapeutics function by inhibiting the target protein. Recent research has shown that, in many cases, achieving the degradation of the target protein is more effective than merely pharmacologically inhibiting it. This proposal focuses on the development of "Modular degradation of extracellular proteins" (MoDEs) designed to enable the removal of extracellular proteins from circulation. Through the proposed research program, we will (1) develop improved MoDEs with more favorable, druglike properties, (2) establish a high-throughput assay and rigorous mathematical framework for evaluating MoDE candidates to accelerate development cycles, and (3) demonstrate MoDE efficacy in an autoantibody-driven animal model of autoimmune disease. This research will pave the way for the future clinical development of MoDEs to treat antibody-driven autoimmune disorders and heart failure. To accomplish this, we have created and tested bifunctional molecules with the capability to selectively deplete antibodies based on their epitope specificity, while preserving the remainder of the immunoglobulin repertoire. This technology relies on bifunctional small molecules, composed of a target-binding portion linked to a ligand for the asialoglycoprotein receptor (ASGPR) on hepatocytes via a spacer. Upon the administration of these compounds, a ternary complex is formed among the target protein, the bifunctional molecule, and the ASGPR on the surface of liver cells. This complex is subsequently internalized into endosomes, leading to the trafficking of the target protein to lysosomes for degradation. To develop improved MoDEs, we will use computer-assisted molecular modeling and medicinal chemistry to adapt these novel ASGPR ligands into wholly small-molecule MoDEs. We expect that MoDEs incorporating the small molecule ASGPR ligands discovered in our laboratory will exhibit improved affinity, oral bioavailability, ease of large-scale production and profound improvements in PK/PD properties. To accelerate the future development cycles of MoDEs, we will develop a bioluminescence-based high-throughput assay for target protein endocytosis and lysosomal trafficking, as well as a mathematical model of the kinetics of the intracellular process underpinning MoDE-dependent degradation. Finally, we will develop and test MoDEs that incorporate antigen mimics to selectively eliminate pathogenic autoantibodies associated with heart failure while preserving the healthy antibody repertoire.