Lead Chief Investigators: Greg Challis and Max Cryle, Monash University
Collaborating Chief Investigators: Gottfried Otting, Colin Jackson, Lara Malins, Richard Payne
Epoxyketone-containing nonribosomal peptides produced by bacteria, such as epoxomicin and eponemycin, are potent proteasome inhibitors that have inspired the development of several drugs. These include carfilzomib, an intravenously administered synthetic peptidyl epoxyketone that is FDA-approved for the treatment of multiple myeloma; oprozomib, an orally active multiple myeloma treatment currently in phase 1b/2 trials; and KZR-616, a selective inhibitor of the immunoproteasome undergoing phase 1b/2 trials for the treatment of lupus. This project aims to develop a better understanding of key epoxyketone biosynthetic enzymes with the long-term aim of developing sustainable biocatalytic processes for the manufacture of peptidyl epoxyketones.
Relevance to the Centre
This project aims to decode the mechanisms for assembly of epoxyketone-containing nonribosomal peptides in bacterial cells and harness epoxyketone biosynthetic machinery to develop more sustainable approaches for the production of peptidyl epoxyketone drugs used in the treatment of cancer and drug candidates designed to treat autoimmune diseases. The project is thus fully aligned with the Centre’s vison.