University of Bath
A High Throughput Screen to Derive Functional Antagonists of Transcription Factors
There are many library-based approaches that can screen for protein-protein interaction, PPI, inhibitors. However, none guarantee functional loss of the target protein. Using the oncogenic transcriptional regulator Activator Protein-1, AP-1, as our exemplar, we have developed a novel intracellular Transcription-Block Survival, TBS, screening assay, which can ensure functional loss of the target protein. TBS works by ensuring that gene transcription is blocked, which is only restored if inhibitors bind AP-1 and prevent its DNA binding activity to restore cell viability.
This ability to distinguish between non-functional binders and those capable of blocking DNA-binding function is unique and addresses a problem that has hampered the search for 'functionally active' inhibitors. Intracellular screening additionally removes toxic, insoluble, protease susceptible, or non-specific compounds from the screen, accelerating progress towards clinical trials.