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, expanding the repertoire of limited ligands and degradation pathways available for PROTACs.

Non-degrading Type I molecular glues, FK506, Cyclosporin, and Rapamycin, have delivered marketed therapies. The complex structures of these molecules have limited application to only a limited number of protein targets. The presentation will describe construction of DEL and array libraries of non-degrading molecular glues used for finding chemical starting points for a wide range of intracellular targets. Concepts of topological diversity, cell permeability, and molecular glue characterization will be described.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. Given its mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need.

Human Antigen R (HuR), encoding by ELAVL1, binds and stabilizes mRNAs encoding oncogenic drivers and proinflammatory cytokines. Using our GlueXplorer discovery platform, we have identified novel CRBN-based molecular glue degraders of HuR, a previously undruggable target, and determined BRAF mRNA as one of its major direct targets in cancer cells. A preclinical candidate has been selected for development, and this first-in-class program is moving to clinical testing.

Targeting PolΘ through degradation (glue or PROTAC) may provide the opportunity to ablate PolΘ entirely, which mimics the biological consequences of a PolΘ genetic knockout. We shall present in vitro and in vivo data of our first-in-class degrader of PolΘ for the first time.

Sickle cell disease affects millions of people worldwide, disproportionately in resource-limited regions. The development of a widely-accessible, oral fetal hemoglobin (HbF) inducer has long been a goal. Here we leveraged a chemical library of CRBN-biased molecular glues to explore HbF reactivation. Phenotypic screening identified the transcription factor WIZ as a previously unrecognized repressor of HbF. Chemical optimization generated potent WIZ degraders, which were well-tolerated and induced HbF in preclinical models.

Transcription factors (TFs) are among the most frequently mutated and/or translocated genes in cancer, suggesting that a detailed understanding of their mechanism-of-action could better define disease etiology and help identify novel nodes for therapeutic intervention. Recently, our lab has employed novel degron technologies to rapidly degrade TF proteins. This technology, when combined with nascent transcript sequencing and multiomic readouts, allows us to identify direct mechanisms of TF action.

STAT3 is a transcription factor and a promising therapeutic target for cancer and other human diseases. We have discovered a highly potent, selective, and efficacious STAT3 degrader UM-STAT3-1218. UM-STAT3-1218 is a highly promising STAT3 degrader for the treatment of human cancers and other human diseases in which STAT3 plays a key role.

The Jian Jin Laboratory at Icahn School of Medicine at Mount Sinai is a leader in discovering novel degraders targeting oncogenic proteins and developing new technologies for advancing targeted protein degradation and stabilization. Our lab’s recent progress will be presented featuring our latest studies such as Methyl-PROTAC, Z-PROTAC, and more.

Cell target engagement provides a unique rationale for discovery of drug candidates to challenging targets, such as transcription factors, whose functional and structural integrity depend on the complex proteomic context inside the cell. MICRO-TAG cell target engagement platform enables discovery, validation and real-time analysis of novel therapeutics within the cellular milieu. When combined with DELs, the platform can discover chemical matter that pertains to the unique disease-driving state of the target.