Leveraging induced proximity and degradation proteomics, we discovered a novel CRBN-based molecular glue degrader of HuR/ELAVL1, an RNA binding protein abnormally activated in cancer and other diseases. The molecular glue degrader is moving to the clinics to treat BRAF mutant cancers as a monotherapy, while its efficacy in other disease models, including cancer cachexia, has been validated. The mechanistic studies of HuR degrader in these diseases are going to be discussed.

We describe the application of AlphaSeq, a high-throughput, highly sensitive experimental platform for measuring protein-protein interactions, to elucidate >100 novel interactions between therapeutically relevant targets and diverse set of ligases. We further characterize these PPIs through site-directed mutagenesis to prioritize actionable pairs for rational molecular glue discovery. Finally, we depict the systematic AlphaSeq validation and hit-finding approaches we have employed to identify small molecules that enhance these weak ligase-target interactions.

Immunomodulatory drugs (IMiDs) such as lenalidomide and pomalidomide are clinically approved. Although efficacious, IMiDs have been linked to adverse events. Proteolysis-targeting chimeras (PROTACs) have incorporated IMiD substructures and therefore carry an associated inherent liability. Using in vitro assays and proteomics-based readouts, we implemented a robust profiling cascade.

We discovered novel CRBN molecular glues that selectively induce the degradation of VAV1, a key target in cancer and autoimmune diseases. We identified a non-canonical "RT-loop" degron in VAV1, distinct from previously known motifs, expanding the landscape of CRBN neosubstrate recognition. This work, integrating proteomics and computational modeling, demonstrates how chemical modifications can enhance potency and provides a new strategy for designing next-generation VAV1-targeting therapeutics.

Degrading av integrins from the cell surface may provide an advantage over the clinically-failed cancer therapeutics developed to date that merely disrupt the integrin-extracellular matrix interactions. We engineered two integrin degraded to study degrading versus functional blocking alone. We show both mechanisms of degradation have a stronger anti-proliferative effect than ligand blocking alone and modulate downstream signaling proteins that promote tumor development.

Monovalent degraders are molecules that can induce target degradation without containing known ligase binding motifs. As the rules by which these molecules can induce degradation are poorly understood, they are typically found serendipitously. I will describe a systematic drug discovery campaign that led to a potent monovalent degrader of BRM, an important lung cancer target. Furthermore, I will show that this molecule works by covalently recruiting the ligase FBX022.

CREB binding protein (CBP) and E1A binding protein P300 (EP300) are paralog lysine acetyltransferases that function as transcriptional coactivators. Their bidirectional synthetic lethal relationship creates a unique therapeutic opportunity for selectively targeting CBP in EP300-mutant cancers. We demonstrate the potent antiproliferative activity of our selective CBP degraders, both as single agents and in the context of select combination therapies.

Proteolysis-targeting chimera (PROTAC) that selectively eliminates detrimental proteins represents a promising therapeutic strategy for various diseases. We have developed a set of PROTACs with the short and interchangeable degradation signals that attract several distinct E3 ubiquitin ligases. We demonstrate the utility and efficacy of these mini-PROTACs in vitro and in vivo against several oncogenic drivers, expanding the repertoire of limited ligands and degradation pathways available for PROTACs.