Despite the preclinical success of inhibitor development for B-Cell Lymphoma 6 (BCL6) and Bromodomain and Extra-Terminal (BET) proteins, no therapies targeting BCL6 or BETs have been approved to date. Leveraging the benefits of chemically induced proximity, we developed a RIPTAC (Regulated Induced Proximity Targeting Chimera) that simultaneously engages BCL6 and BETs. Contrary to a prior study of TCIP1, we determined that BET loss-of-function is the pharmacological basis of compound activity.

The Jian Jin Laboratory at the 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 work, such as Bridged-PROTAC, DUBTAC, and AceTAC.

A principle in the development of cancer therapeutics is that robust and selective death of the malignant cell is critical. I will present an approach that leverages chemically induced proximity to rewire oncogenes to activate apoptosis in a lineage-specific manner, using molecules termed transcriptional/epigenetic chemical inducers of proximity (TCIPs). These small molecules redirect epigenetic regulators to selectively activate cell-death genes silenced by cancer drivers such as BCL6 in lymphoma.

TP53 mutations drive ~50% of cancer deaths, typically via missense mutations that paradoxically increase p53 protein. We exploited this abundance using an induced proximity strategy: a bifunctional molecule linking a TP53-Y220C binder to a PLK1 inhibitor concentrates toxicity selectively in mutant cells. The resulting ternary complex mislocalizes PLK1, induces G2/M arrest, and triggers apoptosis in TP53-Y220C cells while sparing wild-type, offering a generalizable framework for targeting missense mutant p53.

This talk covers the discovery of molecular glues that reprogram the E3 ubiquitin ligase TRIM21 to degrade the nuclear pore complex (NPC). Phenotypic and functional genomic screens revealed that TRIM21 mediates the response to a clinical-stage drug. Proximity proteomics and biochemistry demonstrated that the molecular glue induces proximity between TRIM21 and NUP98, resulting in NPC destruction and cancer cell apoptosis. This presents a promising therapeutic avenue for solid-tumor therapy.

Targeting cancer specific dependency has been appealing but challenging task for drug discovery, particularly, transcription factors. We leverage our ability on chemical biology to target an unique cancer dependency, IRF4, a particularly compelling target in multiple myeloma. We developed the first potent and selective small-molecule binder of IRF4 and converted it into an IRF4-targeting degrader, establishing that direct chemical engagement of IRF4 is feasible for therapy development.

The spatial organization of membrane proteins shapes cellular function, yet target discovery largely relies on protein expression alone. We introduce MetaMap, an analytical framework leveraging proximity-informed graph learning to define spatial protein communities across tumor cell surfaces. By integrating these spatial networks with deep learning, we identify "Tumor-Associated Proximity Antigens" (TAPAs)—revealing novel, disease-specific co-targets for precision multispecific therapeutics.

GlueFinder accelerates molecular glue discovery by systematically mining the Protein Data Bank for ligandable pockets adjacent to protein–protein interfaces that can nucleate glue-stabilized ternary complexes with E3 ligases. Benchmarking on solved dimers supports its ability to recover known and propose new glues. Applied to EGFR, HER2, and KRAS, GlueFinder predicts candidate glues recruiting 24, 111, and 148 distinct E3 ligases, respectively, and can induce non-native EGFR complexes.