Transcriptional regulators are promising but challenging targets for drug discovery and development. Dynamic conformational changes, a high degree of intrinsic disorder in structure, and multiple binding partners pose challenges to identify functional binders. In addition, transcriptional modulators could regulate several downstream pathways by controlling gene expression. Here, I will discuss multiple strategies taken to identify pathway-specific biased modulators to impact a specific signaling pathway.

Previously “undruggable” transcription factors tend to fold and function properly only within native cellular environments. To address these targets, we developed TF-Scan, a live-cell assay that measures changes in TF DNA-binding activity after small molecule treatment. Using TF-Scan, we discovered covalent compounds capable of binding and inhibiting dozens of previously undruggable TFs. This was followed by rapid optimization of a lead brachyury inhibitor that blocks chordoma tumor growth in vivo.

For many difficult to drug targets, the milieu of the native cellular environment is critical to capturing the relevant biological state for ligand discovery. Alkyne-bearing electrophiles offer a flexible toolset for in-cell assay development, including both mass spectrometry (MS)-based and non-MS based approaches toward binder discovery for transcription factors and beyond.

WDR5 is a co-factor for MYC oncoprotein transcription factors and an auspicious target for anti-cancer drug development. We have discovered small molecule inhibitors of the "WIN" site of WDR5 that are highly potent, orally bioavailable, and active against multiple cancer types in preclinical studies. I will discuss our recent efforts to define the optimal strategies for implementation of WIN site inhibitors for the future treatment of solid and hematologic malignancies.

Transcription factors are historically a challenging target class to drug. Although DNA-encoded libraries (DEL) have become a staple for ligand discovery, transcription factors and other proteins that specifically bind DNA present distinct challenges for DEL technology. Nurix has developed a broadly applicable approach for applying affinity selection and informatic methods to transcription factors, and these methods have yielded tractable hits for the EWS-FLI1 fusion oncoprotein.

Transcription factors (TFs) make for compelling drug targets but have been historically hard to drug. In disease settings, TFs can hijack the BAF chromatin remodeling complex to open incorrect regions of the genome, promoting the diseased state. Here we highlight how Foghorn’s transcription factor platform has been set up to understand TF-BAF interactions, develop various HTS assays, and find chemical matter for the disruption of protein-protein interactions.

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.