posted on 2015-12-16, 21:07authored byDennis
L. Buckley, Inge Van Molle, Peter C. Gareiss, Hyun Seop Tae, Julien Michel, Devin
J. Noblin, William L. Jorgensen, Alessio Ciulli, Craig M. Crews
E3 ubiquitin ligases, which bind protein targets, leading
to their
ubiquitination and subsequent degradation, are attractive drug targets
due to their exquisite substrate specificity. However, the development
of small-molecule inhibitors has proven extraordinarily challenging
as modulation of E3 ligase activities requires the targeting of protein–protein
interactions. Using rational design, we have generated the first small
molecule targeting the von Hippel–Lindau protein (VHL), the
substrate recognition subunit of an E3 ligase, and an important target
in cancer, chronic anemia, and ischemia. We have also obtained the
crystal structure of VHL bound to our most potent inhibitor, confirming
that the compound mimics the binding mode of the transcription factor
HIF-1α, a substrate of VHL. These results have the potential
to guide future development of improved lead compounds as therapeutics
for the treatment of chronic anemia and ischemia.