Cyclica, a company specializing in data-driven drug discovery, has determined that the lung-cancer drug capmatinib shows evidence of attenuating the impact of coronavirus. The firm made the discovery via collaboration with Ryerson, the Vector Institute, and other Canadian institutions; funding came through COVID-19 grants from the Canadian Institute for Advanced Research (CIFAR) and Natural Sciences and Engineering Research Council of Canada (NSERC) Alliance COVID-19 grants, with funding support from FedDev Ontario.
Capmatinib is an FDA-approved MET inhibitor, marketed by Novartis under the name Tabrecta; the treatment is used in clinical applications to treat patients with non-small-cell lung cancer. According to the researchers, testing capmatinib in a collection of experiments evaluating viral infectivity, entry and mechanism showed promising results.
“By targeting human proteins necessary for the coronavirus lifecycle, we are developing therapeutic strategies applicable to future strains or variants,” said Bo Wang of the Vector Institute. “Unlike high throughput screens, accurate AI predictions aimed at specific human-based, antiviral targets provided us with a risk-adjusted strategy to search for drug-repurposing opportunities using scientifically accurate experiments with high biological relevance.”
In Canada, infection rates recently surpassed the 1m mark, with deaths are at more than 23,000 and counting. With the world reaching 132m infections and nearly 3m deaths, life-sciences professionals are keen to discover new potential interventions.
Each of the research institutions contributed a different resource to further the discovery. The Vector Institute team’s graph convolutional network (GCN) identified possible human targets relevant to COVID-19, which fed into Cyclica’s PolypharmDB database for finding repurposing opportunities, which were generated using Cyclica’s deep learning approach MatchMaker. Multiple candidate treatments were identified with the technology, with capmatinib showcasing prominent activity.
Costin Antonescu, from the Department of Chemistry and Biology at Ryerson University, said capmatinib’s activity was independent of its known target MET, with evidence pointing towards its inhibition of the IRAK1/IRAK4 pathways.
“COVID has highlighted how important repurposing discoveries are to the future of medicine,” said Antonescu. “These drugs move to clinical trials and through regulatory approval quickly and can therefore reach patients faster; we’ve found a drug that has demonstrated robust antiviral activity in our model systems and we look forward to getting this data in the hands of pharma."
Antonescu added, “There is still much to learn about the etiology of COVID-19, and unraveling the dichotomy of the IRAK pathway as both protective against infections but also critical for viral proliferation may be an important piece to combating this terrible disease.”
This research is a part of the Cyclica COVID Stimulus Program. Launched in March 2020, the project involved engaging in a multi-institution collaboration to use a full-stack AI approach to identify a non-obvious repurposing candidate for COVID-19.
“Our goal with the COVID Stimulus Plan was to make a measurable impact on patient lives today through proposing new therapeutic candidates, as well as advance our understanding of COVID-19 and other related diseases,” said Cyclica CEO Naheed Kurji. “This is important as in addition to COVID-19, two additional coronaviruses were responsible for deadly outbreaks in the past 20 years that had pandemic potential.”