Reports of research work funded by grants prior to 2014
Victoria University of Wellington
Marine Natural Products
JH Miller and PT Northcote
Centre for Biodiscovery and School of Biological Sciences
Our laboratory is continuing its research on peloruside, a microtubule-stabilising agent that works in a similar fashion to the clinically effective chemotherapy drugs like the taxanes: paclitaxel and docetaxel. This drug class is useful in reducing the growth of solid tumours, in particular, breast, lung, and ovary. As these drugs have significant side effects on patients and because long-term treatment induces resistance to the drugs, are attempting to develop peloruside as a possible supplement to taxane therapy. An exciting development in the peloruside programme was the recent determination of the crystal structure of peloruside (and another related microtubule stabilising agent, laulimalide) bound to its protein target tubulin. This significant advance was published in a leading chemistry journal, Angewandte Chemie Intl Ed. Researchers had previously proposed that peloruside stabilised microtubules in a different way to the taxanes. The bound crystal structure confirmed a unique binding site for peloruside that was shared by laulimalide. It also highlighted an inter-protofilament binding interaction for these two compounds. These unique features and the improved tolerability of peloruside in preliminary animal testing provide support for its further development as an anticancer agent. Important directions for our research in the future, in association with the Ferrier Institute, are: a) to examine the pharmacokinetics of peloruside either in cultured cancer cells or in intact mice, and b) to develop a synthetic strategy to chemically synthesise clinically relevant amounts of the compound. In addition, Assoc Prof Peter Northcote of the School of Chemical and Physical Sciences continues to identify new peloruside analogues in marine sponges that are helping us examine structure-activity relationships. We are currently attempting to link structural modifications to the inter-protofilament binding of the two compounds. This information could identify important functional differences between peloruside and the taxanes, since the taxane drugs lack this inter-protofilament binding activity.
In addition to the peloruside/laulimalide research, we are currently studying another microtubule-stabilising agent from avocados, persin, in conjunction with Dr Darby Brooke of the Cawthron Insitute. The structure of persin neither resembles the plant-derived taxanes nor the sponge-derived pelorusides and laulimalides. It displays micromolar anti-proliferative activity in cultured cancer cells. A manuscript on this compound is being prepared for publication.
A third type of marine sponge compound, hamigeran G, was previously shown by us, using chemical genomic barcode microarray screens in yeast, to target Golgi secretory function and vesicular trafficking. We are currently attempting to validate this mode of action for hamigeran G in cultured human cancer cell lines. The inhibitory activity of hamigeran G, like persin, is in the low micromolar range, rather than the nanomolar range of peloruside and laulimalide. We have an extensive set of hamigeran derivatives that have differential growth inhibitory activity, but hamigeran G is the most active of these derivatives. The analogue set will be useful for determining structure-activity relationships, once the mode of action of the hamigerans is confirmed.