The drug, PWT33597, is a dual inhibitor of phosphatidylinositol-3-kinase (PI3K) alpha and mTOR, two key molecules implicated in cancer. It is the first agent with this biological profile to enter the clinic. Initially, a Phase I trial will evaluate the safety of escalating doses of PWT33597 in patients with advanced solid tumours.
Medicinal chemist Professor Bill Denny and cell signalling expert Professor Peter Shepherd, both of The University of Auckland and Maurice Wilkins Centre for Molecular Biodiscovery, established Pathway Therapeutics in New Zealand in 2008 to develop inhibitors of PI3K to treat cancer. The company’s development was guided by Auckland UniServices Ltd and benefited from a significant investment from the Breast Cancer Research Trust. The company has now moved to San Francisco but still has a significant level of New Zealand shareholding.
The PI3K drug discovery programme originated from research funded by the Health Research Council of New Zealand and the Maurice Wilkins Centre, which brought together Professors Denny and Shepherd and their research teams from the Auckland Cancer Society Research Centre and the Signal Transduction Laboratory, respectively. The Maurice Wilkins Centre also facilitated their research by providing long-term salary support of key scientists in the PI3K inhibitor programme and providing infrastructure critical for developing the drugs.
“The announcement that PWT33597 will proceed to clinical trials is a significant milestone for the PI3K inhibitor programme established in New Zealand,” says Professor Rod Dunbar, Director of the Maurice Wilkins Centre. “It is an indication of the strength of drug discovery in this country and the standing of New Zealand science on the international stage. It is also a very tangible example of the value of interdisciplinary collaboration in tackling complex scientific problems.”
“Developing drugs to block PI3K is a ‘hot topic’ in international cancer research. Mutations in PI3K alpha are some of the most common genetic abnormalities in human cancers, especially breast, ovarian and colon cancers,” explains Professor Shepherd “Because of this it is thought that PI3K inhibitors will be potentially effective against a wide range of tumour types and have the potential to be “blockbuster” drugs.”
“Our novel drug, PWT33597, inhibits not only PI3K alpha but also mTOR, one of the most important molecules activated by PI3K,” says Professor Denny. “Inhibiting the activity of both proteins provides a back-up should cancer cells find a way to overcome either one of the blockades. Our preclinical research has shown that PWT33597 very effectively inhibits the critical signalling pathway that these two molecules regulate.”