Target acquired for previously undruggable transcription factor

Transcription factors are a class of proteins that interact with DNA to regulate gene expression. They’re also implicated in many cancers. For years, scientists have considered transcription factors to be undruggable, but new research published this month in Molecular Cell shows they may be druggable after all (2024, DOI: 10.1016/j.molcel.2024.09.024).

Michael Erb, a chemical biologist at Scripps Research and coauthor on the paper, tells C&EN that transcription factors were previously considered undruggable because they “don’t have the types of surfaces that medicinal chemists and drug hunters are accustomed to finding small molecules for.” The transcription factor FOXA1 has been one of the most coveted targets for a drug because it is implicated in the growth of breast and prostate cancers, according to Erb.

Erb’s lab, in collaboration with Scripps colleague Benjamin Cravatt, used a technique called activity-based protein profiling (ABPP) to discover a ligand that interacts with FOXA1. The team used ABPP and promiscuous electrophiles to probe proteins for potential ligand binding sites, Erb says. Then the researchers looked for small molecules that stereoselectively interact with those binding sites.

That search led them to a tryptoline-scaffolded acrylamide, WX-02-23, that interacts with cysteine-258 of FOXA1 when FOXA1 is bound to DNA. This interaction relaxes FOXA1’s DNA-binding sequence specificity and changes genome organization. This proves that transcription factors can be drugged, which may lead to new medicines, Erb says.

Georg Winter, a chemical biologist at the Research Center for Molecular Medicine of the Austrian Academy of Sciences, calls the work “paradigm shifting” and says that it has “tremendous implications for our understanding of and ability to pharmacologically modulate transcription regulation.”