The University of Melbourne
Project Term: October 1, 2021 - September 30, 2024
We have identified the multi-domain protein DCAF1 as a genetic dependency in multiple myeloma and developed a series of potent on-target DCAF1 inhibitors that have a unique mode of action compared with existing therapies. In this proposal we will continue the detailed molecular characterization of our lead compound Vpr8. In parallel, using Vpr8 as the scaffold, we will develop a new series of PROTAC drugs that engage the ubiquitin ligase activity of DCAF1-containing E3 complexes.
Multiple myeloma (MM) is a common blood cancer with an increasing incidence in Australia and the US. Treatment outcomes in MM have significantly improved with the introduction of novel (non-chemo) treatments, in particular those targeting the way the cancerous plasma cells process proteins internally (for example thalidomide and its analogues – the ‘IMiDs’). Unfortunately, despite initial clinical responses, the majority of patients relapse with treatment-resistant disease and MM is considered incurable. New therapeutic approaches that are active in treatment-resistant disease are urgently required. Using gene-editing technology called CRISPR, we looked for essential components of MM cell protein processing machinery and identified that a protein called ‘DCAF1’ is required to keep MM cells alive. DCAF1 has multiple functions in addition to protein processing so we performed more detailed CRISPR analysis and identified the precise parts of DCAF1 that could be inhibited to kill MM cells. The medicinal chemists in our team then devised a series of drug prototypes that could inhibit DCAF1 and we tested >50 of these on MM cells to identify the most potent potential agents in this new class. Importantly, our lead DCAF1 inhibitor (Vpr8) is very potent and kills both MM cell lines and MM cells from patients. This includes MM cells that are resistant to chemotherapy and IMiDs. Our group is now positioned to translate Vpr8 to early phase clinical studies, but more work is required to make this critical step forward. The research questions and aims of this project are required to progress our new drug class closer to deployment in the clinic: Aim 1: How exactly does Vpr8 kills the MM cell and can we develop laboratory tests to identify the downstream targets of Vpr8 in MM cells? Aim 2: Can we hybridise Vpr8 to other molecules to develop protein degraders, a class of drugs that enables destruction rather than inhibition of molecular targets? Aim 3: Develop a compelling translational data set by testing Vpr8 and derivatives in more preclinical models of MM. This aim will include more extensive testing of our inhibitors on MM cells from patients, including those with disease that is relapsed or refractory to established MM therapies. We will also build on our promising initial data by modelling treatment responses in mice, using sophisticated and clinically relevant MM models.