Changing the Game in Cancer Drug Discovery: Removing Disease-Causing Proteins with Surgical Precision
Harald Weinstabl, Head of Medicinal Chemistry
Peter Ettmayer, Head of Drug Discovery Sciences
Darryl McConnell, Research Site Head Austria
“The promise of protein degraders is that they offer real hope for creating drugs against disease-causing proteins that have previously been considered undruggable, bringing challenging targets such as all KRAS mutants potentially within reach,” says Darryl McConnell, Boehringer Ingelheim’s Research Site Head, Vienna, Austria. This bold approach is fundamental to the Company’s oncology research strategy which aims to lead scientific discovery by fighting cancer on two fronts: attacking cancer cells directly and boosting the immune system against cancer through immuno-oncology approaches. The goal for the protein degrader research team is to create first-in-class drugs for patients for whom there are currently very limited treatment options.
Protein degraders offer a novel and potentially highly-effective way to address so-called undruggable targets, such as KRAS, by harnessing the power of the cell’s natural waste disposal system to selectively eliminate cancer-causing proteins. “Using fragment-based drug discovery has enabled us to probe the well-hidden, shallow binding pockets on KRAS to discover not only G12C and G12D selective inhibitors but also so-called pan-inhibitor and degrader molecules that can hit all the major KRAS mutations that drive cancer rather than picking them off one by one,” says McConnell. And that’s why protein degraders play a key role in Boehringer Ingelheim’s KRAS research strategy.
“With protein degraders we can expand the cancer patient population we treat, beyond those with specific KRAS mutations, to people with cancers driven by other KRAS mutations, with the exciting potential of targeting more than 60% of oncogenic KRAS mutants with one drug,” explains Peter Ettmayer, Head of Drug Discovery Sciences at Boehringer’s Research site in Vienna. “They fuse the disease-causing protein of interest – in this case KRAS - to a hijacked ligase of the cell’s proteosomal degradation machinery. This triggers ubiquitination, which tags the protein with the proteasomal ‘kiss of death,’ marking it for destruction.”
A Precision Approach to Protein Degradation
Boehringer Ingelheim researchers are drawing on their structure-based expertise as they work to develop these innovative cancer destructors. “Precision is at the heart of our approach. We use biophysics to first get a foot in the door against a new target and then apply structure-based design to discover highly potent degraders,” reflects McConnell. “This enables us to identify degrader leads against tough to drug targets like KRAS which would otherwise be missed by a more serendipitous approach.”
"Leading the field in structure-based and co-operativity-driven degrader design is our key strength in this field,” agrees Ettmayer. “Rather than taking an indiscriminate approach by making hundreds of compounds and hoping one fits, we generate ternary structures (target-PROTAC-ligase) and then design the right molecule to fit into the pocket formed by two proteins. Ultimately this accelerates discovery times with the potential to get new medicines to patients faster.”
Three research approaches:
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Partnering with Pioneers
Collaborations with world-leading groups in protein degrader identification and design are a key element of Boehringer Ingelheim’s ambition to be a leader in pan-KRAS approaches. “The field is exploding – and there are smart minds working on this – so to be fast in getting new drugs to patients it’s essential to collaborate and share our expertise,” says McConnell. “We collaborate with pioneers with ‘like minds’: with science at the core and a real ambition to translate this into drugs that tackle even the most difficult targets in cancer. Results-oriented team science is the way we work together.”
A partnership with one of the world’s pioneers in PROTACs, Professor Alessio Ciulli, and his team at the University of Dundee, Scotland, is revolutionizing structure-based design of PROTACs. “The initial aim was to develop and apply a rational approach to PROTAC drug development, based on a fundamental understanding of how they work,” recounts Harald Weinstabl, Head of Medicinal Chemistry, Boehringer Ingelheim Regional Center Vienna. “The structural characterization of PROTAC ternary complexes has proved a real game changer in the identification and optimization of PROTACs against KRAS and other previously undruggable targets.”
The joint team reported their approach of using three-dimensional pictures at atomic resolution to design highly-selective and potent PROTAC candidates in Nature Chemical Biology1. Their structure-based design approach is already bearing fruit, resulting in the first PROTAC shredding SMARCA2, an important cancer driver.
Weinstabl, whose Medicinal Chemistry department closely interacts with the collaboration partners, attributes this success to the two groups working as equal partners in a spirit of trust, openness and sharing. “We work to common goals and ensure both partners can play to their strengths.” And this is paying dividends. “We have already achieved multiple preclinical milestones, most notably we have identified pan-KRAS degraders that selectively kill KRAS-mutated cell lines.”
A further collaboration with the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, Australia, is focusing on inhibitor of apoptosis (IAP) proteins. “IAPs have very complex pharmacology, so WEHI, where Professor John Silke is a world-renowned expert in the field, is the ideal partner for Boehringer Ingelheim to take IAP-based protein degraders to the next level,” suggests Weinstabl.
Another type of molecular degrader, along-side PROTACs, are molecular glues. They are much smaller than PROTACs and hence easier to make into orally dosed drugs. Identifying molecular glue degraders has been largely serendipitous up to this point, but a collaboration with Proxygen is bringing together the company’s highly scalable and broadly applicable molecular glue discovery platform with Boehringer Ingelheim’s experience in innovative oncological research to systematically screen for novel molecular glue degrader candidates for various targets.
And a collaboration with PhoreMost is harnessing the power of its next-generation phenotypic screening platform to explore disease-relevant pathways nominated by Boehringer Ingelheim. In cells, proteins adopt specific conformations forming cellular complexes that cannot be observed using purified components. For oncology, scientists will use the platform to identify novel druggable binding interfaces required for the action of oncogenes.
Potential for Patients
With the discovery of pan-KRAS degraders currently in the research phase, Boehringer Ingelheim is encouraged by the promise of these novel drugs. “The power of protein degraders against KRAS and other key oncogenes for cancer patients who currently lack effective treatment options is mind-boggling,” concludes McConnell. “They provide the potential to address resistance, provide tissue specificity and in the case of KRAS to degrade all the major oncogenic mutants with just one degrader.”
Footnotes
With thanks to Mark Pearson, Head of Cancer Cell Signaling, Boehringer Ingelheim for additional contributions.
References
1. Farnaby W, Koegl M, Roy MJ et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nature Chemical Biology 2019; 15: 672-680
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