Lead Chief Investigators: Greg Challis and Max Cryle, Monash University
Collaborating Chief Investigators: David Fairlie, Colin Jackson, Gottfried Otting, Lara Malins, Richard Payne
Bicyclic depsipeptide natural products from bacteria potently and selectively inhibit class I histone deacetylases (HDACs). They display promising anticancer activities, as exemplified by romidepsin, which is approved by the FDA for the treatment of cutaneous and peripheral T-cell lymphoma. However, their biosynthesis is poorly understood. This project aims to decode the biosynthetic mechanisms of these bicyclic depsipeptide HDAC inhibitors and discover and develop novel structural derivatives with improved therapeutical potential.
Relevance to the Centre
This project aims to exploit genomics-driven approaches to discover novel bicyclic depsipeptide natural products that inhibit of class I histone deacetylases – an important target for cancer chemotherapy. Decoding the mechanisms of assembly for these clinically important metabolites, will enable us to implement biosynthetic and chemoenzymatic strategies for the production of novel analogues, which will illuminate structure-activity relationships and accelerate the development of novel drug candidates. The project is thus fully aligned with the Centre’s vison.