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Chem Sci. 2017 Jun 1;8(6):4612-4618. doi: 10.1039/c7sc00137a. Epub 2017 Apr 27.

Controlled inhibition of methyltransferases using photoswitchable peptidomimetics: towards an epigenetic regulation of leukemia.

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Fachbereich Chemie , Philipps-Universität Marburg , Hans-Meerwein-Strasse 4 , 35043 Marburg , Germany . Email:
Department of Pathology , University of Michigan , Ann Arbor , Michigan 48109 , USA.
LOEWE Zentrum für Synthetische Mikrobiologie SynMikro , Philipps-Universität Marburg , Hans-Meerwein-Strasse 4 , 35043 Marburg , Germany.


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 (Ki = 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.

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