In an article published today in the prestigious journal Nature Chemical Biology, scientists at the University of Dundee and Boehringer Ingelheim have made an important first stride toward drugging undruggable cancer targets using an innovative approach to drug discovery.
The discovery marks a first milestone of a major collaboration between Alessio Ciulli, Professor of Chemical and Structural Biology at the University of Dundee’s School of Life Sciences and a leader in the emerging field of targeted protein degradation, and the pharmaceutical company Boehringer Ingelheim. Since its establishment in 2016, the collaboration has innovated novel approaches to design and develop Proteolysis targeting chimeras (PROTACs) as drugs against cancer.
PROTACs work by hijacking the cell’s natural disposal system (the ubiquitin-proteasome system) to label disease-causing proteins so that the cell’s recycle bin (the proteasome) can rapidly shred them. As such, PROTACs represent a revolutionary new class of drug candidates that are now entering clinical trials. Because they destroy cellular targets, rather than just inhibiting them, PROTACs have the potential to reach out to proteins that have not previously being drugged using conventional approaches. However, experimental achievement against such highly prized cancer targets remains a historic challenge.
The “AC-BI” team within the Ciulli group, and their collaborators within Boehringer Ingelheim, Vienna, headed by Darryl B. McConnell, Senior Vice President and Research Site Head, discovered a potent and selective PROTAC compound that rapidly induces degradation of the proteins SMARCA2 and SMARCA4 in cancer cells. SMARCA2/4 are subunits of a large multi-protein complex called BAF, that is involved in regulating gene expression in cells, and is found mutated in approximately 20% of human cancers, including of the lung and ovary. In many of those tumours, SMARCA2 or SMARCA4 drive the proliferation of cancer cells, yet have remained difficult to target using small molecules.
In the publication, Farnaby et al. describe their innovative approach to degrading SMARCA2/4. The team solved high-resolution 3-dimensional structures showing how their designed PROTAC recruits the target protein to the E3 ubiquitin ligase von Hippel-Lindau complex. Next, they used this information to rationally optimize compounds, leading to PROTAC ACBI1, a selective and highly effective degrader molecule. Finally, they showed that ACBI1 potently kills cancer cells, in a highly targeted fashion, as a result of inducing removal of SMARCA2/4 from within cells.
“Our joint publication is a leading example of translating the detailed understanding we are developing of how PROTACs work, to craft molecules that effectively target truly undruggable proteins for degradation.” said Alessio Ciulli. “This work highlights the strides forward such an academia-industry collaboration model can make in the rapidly emerging field of targeted protein degradation’’ explains William Farnaby, team leader within the Ciulli group who is co-first author of the article together with Boehringer Ingelheim’s lead biologist Manfred Koegl. “We hope that the advancements shared here are a step towards treating cancers that rely on SMARCA2/4 for their survival’’
The study is a prime example of modern goal-driven multidisciplinary ‘team science’. Amongst the Dundee SLS co- authors are postdoctoral scientists Michael Roy, Claire Whitworth, Emelyne Diers, Nicole Trainor and David Zollman from the AC-BI team who contributed on medicinal chemistry, crystallography, biophysics, cell biology and proteomics. The study also featured contributions from Professor Tom Owen-Hughes laboratory who are leading experts of chromatin remodelling complexes.
“Our work exemplifies a broadly applicable ‘structure-based PROTAC design’ approach”, said Ciulli. “This approach could serve to accelerate the development of new therapies for intractable cancers”. The collaboration is now focused on expanding the approach to other important cancer targets, and on developing their advanced molecules as lead candidates”.