Small molecule modulators of key necroptosis proteins have been discovered at WEHI and developed through Catalyst Therapeutics (a joint venture between WEHI and SYNthesis Research) and commercialised through a spin-out company, Anaxis Pharma.
WEHI researchers have played a key role in the discovery and broader understanding of necroptosis, having characterised many key molecular mediators of this form of programmed cell death, as well as identifying how this process drives inflammation.
Armed with the conviction that necroptosis was a key contributor of inflammatory pathology, the WEHI team embarked on a drug discovery project to identify small molecule modulators of key necroptosis proteins. Such modulators could have applications for preventing inflammatory conditions such as Crohn’s disease or ischemia reperfusion injury.
The project was initiated in 2014 at WEHI’s drug discovery centre (now the National Drug Discovery Centre). The first inhibitors were licensed to Catalyst Therapeutics, a Melbourne-based ‘venture discovery’ company that is a joint venture between WEHI and SYNthesis Research.
Through this collaboration the inhibitors were honed by structure-guided medicinal chemistry to improve their potency and drug-like qualities. By late 2016, the program had developed into a compelling drug discovery package. The therapeutic mechanism of action of its well-credentialled drug leads was underpinned by WEHI’s deep understanding of the molecular choreography of the necroptosis process.
In 2017 Anaxis Pharma was created as a spinout of Catalyst Therapeutics to facilitate the commercialisation of the program through collaboration with a multinational pharmaceutical company. This multiparty collaboration has since progressed these compounds through the drug development process to the point where they are now close to the selection of a preclinical candidate.
Professor Andrew Wilks, the Chief Executive Officer of Anaxis, said the project leveraged the extensive expertise and capabilities of both WEHI and SYNthesis.
“This was one of the most inspiring collaborations I have ever been involved with,” he said. “Being able to apply the significant medicinal chemistry resources from SYNthesis to the world-leading science that the WEHI team brought to the program has led to something quite extraordinary. The medicinal chemistry phase of the programme has been significantly driven by the insights brought from WEHI’s medicinal chemistry and structural biology teams, and the ‘chemical biology’ of our drug candidates aligns precisely with the biochemical understanding of the necroptosis pathway that the WEHI biology team has wrought. I can’t tell you how satisfying it is when these elements work so well together.”
Access to the drug discovery capabilities available through WEHI’s National Drug Discovery Centre enabled Anaxis to progress the project extremely rapidly, with hit-to-lead optimisation through to lead optimisation occurring in 2019-2020.
“In 2017, Anaxis entered into a partnership with a multinational pharmaceutical company, which enabled us to advance this exciting program more rapidly towards the clinic. This is a fantastic example of how WEHI’s fundamental research discoveries – and WEHI’s preparedness to commercialise them – have underpinned the development of potential new medicines. It was not just the initial hits that WEHI provided, but also their ability to partner with the private sector, and their ongoing commitment to building and enhancing the understanding of what these molecules were doing in the cell, that was so important,” Professor Wilks said.