Targeting Transcription Factors

Transcription factors would be excellent targets for drug discovery in a variety of therapeutic areas except that they lack pockets suitable for tight binding to small molecules. In this session, approaches for overcoming these limitations will be presented, along with examples of targeting key transcription factors involved in disease.

Pharmacologic activation of tumor-suppressor proteins for cancer treatment remains a major challenge. Here, we present a novel Acetylation Targeting Chimera (AceTAC) strategy to activate the p53 tumor suppressor protein via acetylation. We discovered and characterized the first p53Y220C AceTAC, MS78, which effectively acetylated p53Y220C lysine 382 (K382) and suppressed proliferation of cancer cells harboring the p53Y220C mutation. Altogether, AceTAC is an invaluable and powerful chemical biology platform to illuminate the human protein acetylome.

Elevated YAP/TAZ-TEAD activity has been implicated in multiple cancer types at various stages of cancer progression. We report novel small molecule Pan-TEAD inhibitors that form covalent complexes with a cysteine in the TEAD palmitoylation site. Compounds translocate YAP into the cytoplasm and inhibit TEAD transcriptional target genes in cancer cells. TEAD1 dependency of gastric cancer cell lines enhance cellular sensitivity in responses to small molecule Pan-TEAD inhibitors.

Belharra Therapeutics is the next wave in chemoproteomics focused on applying a novel chemistry enabled non-covalent probe library and quantitative mass spectrometry to identify chemical probes that selectively bind any pocket, on any protein, in live cells. The platform is identifying chemical probes that selectively engage diverse protein classes including transcription factors, adaptors, ion channels, and transporters. Most proteins identified as being selectively engaged by our probe library do not have a reported ligand in drug bank demonstrating the ability of the platform to identify novel pockets and potential chemical probe starting points for these targets.

The Hippo signaling pathway is an evolutionarily conserved pathway that plays a role in development and homeostasis. The TEAD family of the transcription factors are the major transcription factors of the Hippo pathway. TEADs regulate many biological processes, including development, tissue homeostasis, and tumorigenesis by regulating cellular proliferation and survival. Identification of the underlying mechanisms to Hippo pathway inhibition would allow us to develop effective combination therapeutic strategies.

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.