E3 Ubiquitin Ligase Inhibitors

While our lab has synthesized and characterized several proteasome inhibitors such as the natural products epoxomicin, eponemycin, fellutamide B and TMC-95A, these inhibitors result in global accumulation of all proteins within cells.  Towards the goal of selective upregulation of targeted proteins, we are interested in developing small molecules inhibitors of E3 ubiquitin ligases.  Our initial focus has been on the design and synthesis of compounds that bind to the HIF binding site on its cognate E3 ligase, the von Hippel Lindau (pVHL) protein.   Our structure-aided design efforts have yielded the current best in class series that binds pVHL with submicromolar affinity.

Relevant Publications:

Buckley DL, Gustafson JL, Van Molle I, Roth AG, Tae HS, Gareiss PC, Jorgensen WL, Ciulli A, Crews CM
Angew. Chem. Int. 2012 51 46 11463-11467
Van Molle I, Thomann A, Buckley DL, So EC, Lang S, Crews CM, Ciulli A
Chemistry & Biology 2012 19 1300-1312
Buckley DL, Van Molle I, Gareiss PC, Tae H-S, Miche J, Noblin DJ, Jorgensen WL, Ciulli A, Crews CM
J. Am. Chem. Soc 2012 134 10 4465-4468