the Myc function in these cell backgrounds. Direct targeting of the Myc transcription factor has long been considered a valuable, but largely intractable approach to treating many different types of cancer. Extensive research has been carried out on Myc��s biological function clearly demonstrating its important role in tumor biology, but no approaches have yet resulted in the successful development of therapeutics that directly target Myc. The intrinsic disorder of the bHLHZip domain of monomeric Myc defies structural characterization approaches such as crystallography, and implies the lack of well-defined binding pockets that could be utilized by small molecules to block its biological activity. As such, Myc has long been considered an undruggable target, and recent attention has instead focused on targeting Myc in an indirect manner. In addition to promising RNAi-based approaches , the recent discovery and characterization of small molecule inhibitors which target the BET family of epigenetic reader proteins have proven to be effective in a Myc context , and they are currently undergoing evaluation in clinical trials. Due to the pan-BET inhibitory profile of these drugs it is likely they will have wide ranging effects beyond selective Myc inhibition, and so it remains unclear what impact this will have on their clinical safety profile. Thus, a potent and selective inhibitor that directly TMC435 targets the Myc protein is likely to have significant clinical utility. We have utilized a novel chemistry platform to identify dimeric inhibitors of Myc. The basis of our approach is to employ bioorthogonal linker chemistries that allow the intracellular selfassembly of two distinct small molecules monomers��each comprising a ligand, a connector and a bioorthogonal linker element��into a large dimeric inhibitor molecule designed to be capable of more potent and selective 1142090-23-0 manufacturer inhibition of protein:protein interaction targets like Myc. The rapidly reversible nature of the linker chemistry under physiological conditions is such that the small molecule monomeric species are amenable to improvements in their absorption from the gastrointestinal tract, distribution to target
