The recent rise of chemically induced proximity-based biology has increased the interest in proteome-wide ligandibility studies and the opportunities that these ligand-target protein pairs create for new modalities or target modulation. Covalent chemoproteomics uses covalent compounds and probes to access information about the cellular protein interactome of a compound and provides granular information about the specific modified amino acid on a target protein; together these data can be viewed in conjunction with a phenotype to determine if the ligand is a functional modulator or silent binder to the protein of interest. Aberrant protein degradation is a pathogenic mechanism in many diseases and as such targeted protein stabilization (TPS), rather than degradation (TPD), would be of therapeutic benefit. Here, as a result of efforts within the Novartis-Berkeley collaboration, which aims to develop new technologies, new modailities and exploit covalency and chemoproteomic approaches we will discuss deubiquitinase-targeting chimeras (DUBTACs). These heterobifunctional small molecules consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand that critically targets a non-catalytic allosteric cysteine and we will describe a DUBTAC consisting of our DUB-recruiter linked to lumacaftor (a drug that binds ΔF508-cystic fibrosis transmembrane conductance regulator), that robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We will also describe chemistry and data supporting this modality as we showcase how covalent chemoproteomic approaches enabled the development of a new induced proximity-based therapeutic modalities.

DUBTAC: The development of a new modality for protein stabilization

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.