Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc00137a Click here for additional data file

Shine light on epigenetics: we describe how photoswitchable peptidomimetics modulate the activity of the MLLl enzyme affecting epigenetic states. We describe a cell-permeable photoswitchable probe capable of modulating epigenetic cellular states by disruption of an essential protein–protein interaction within the MLL1 methyltransferase core complex. Our azobenzene-containing peptides selectively block the WDR5-MLL1 interaction by binding to WDR5 with high affinity ( K i = 1.25 nM). We determined the co-crystal structure of this photoswitchable peptiomimetic with WDR5 to understand the interaction at the atomic level. Importantly, the photoswitchable trans and cis conformers of the probe display a clear difference in their inhibition of MLL1. We further demonstrate that the designed photo-controllable azo-peptidomimetics affect the transcription of the MLL1-target gene Deptor, which regulates hematopoiesis and leukemogenesis, and inhibit the growth of leukemia cells. This strategy demonstrates the potential of photopharmacological inhibition of methyltransferase protein–protein interactions as a novel method for external epigenetic control, providing a new toolbox for controlling epigenetic states.