From idea to clinical trial: a scientific ultra-marathon

Marc Therrien (M. T.): This project originated from a discovery we made in the late 2000s in the fruit fly Drosophila. At the time, we elucidated the mechanism of activation of the RAF oncogene, which is based on dimerization, or the formation of a pair between two RAF proteins. This breakthrough naturally led us to consider developing inhibitors that would block this process. However, this approach proved to be much more complex than expected and has been a major challenge over the past 15 years.

MT: Various sources of funding, notably from the federal government through the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society (CCS), were instrumental in launching the project. This initial phase led to the development of biosensors capable of simply and reliably monitoring RAF dimerization in cells, thereby establishing proof of concept for the identification of compounds that inhibit this dimerization.

We then established a five-year strategic collaboration, from 2012 to 2017, between our team and a pharmaceutical partner and IRIC's drug-discovery unit, thanks to financial support from (the research maturation cluster) IRICoR. This collaboration resulted in a first molecule capable, with certain limitations, of blocking RAF activation. 

From 2017 to 2020 we developed a new series of molecules that are more stable and more diverse, with real potential as lead compounds, that is, compounds whose optimization can lead to new drugs. We also demonstrated for the first time that our molecules were effective in vivo in mice. These milestones would not have been achieved without the support of the SCC and philanthropic contributions.

In 2020, thanks to IRICoR, a new industrial partner was identified: Ipsen, with whom we signed a two-year partnership to optimize our series of compounds with a view to generating a clinical candidate. This partnership mobilized the joint efforts of chemists from the Drug Discovery Unit, led by Pierre Beaulieu, and biologists from my laboratory, led by Hugo Lavoie. At the end of this collaboration, a candidate molecule was selected, leading to the signing of a licensing agreement with Ipsen at the beginning of 2023.

Finally, thanks to preclinical studies conducted in 2023-2024 with (the French biopharmaceutical company) Ipsen, the latter obtained authorization from the Food and Drug Administration in the United States to initiate a phase-1 clinical trial in patients with solid tumors. This clinical trial began in March 2025 at a U.S. hospital and will soon be extended to other sites in the U.S. and Europe.

MT: Their participation was, quite simply, decisive. When it comes to transforming a biological hypothesis into therapeutic chemical entities, expertise in medicinal chemistry is essential: designing, synthesizing and optimizing molecules is a skill that only seasoned chemists can provide. The presence of a sub-team of computational chemists in the drug-discovery unit, who support molecule design (or CADD: computer-aided drug design) through docking techniques, molecular dynamics experiments and machine learning, was also essential in guiding the chemists and accelerating molecule optimization.

Anne Marinier: In drug discovery, synthesized molecules are tested and characterized according to a very precise sequence of biological tests, called an “evaluation tree.” A good candidate progresses through this by meeting predefined criteria for activity and properties. In our medicinal chemistry team, we begin to believe in a molecule's potential when it meets the vast majority of these criteria and, more specifically, when its potency and pharmacokinetic properties allow it to be evaluated in an efficacy model at a dose deemed acceptable. It is this in vivo efficacy study that confirms whether the molecule has real therapeutic potential. In the case of our candidate molecule, the first efficacy studies demonstrating tumor growth inhibition were conducted seven months after its initial synthesis. It was at this point that the team began to have real hope.

MT: Developing a drug is a huge, long-term undertaking that relies on collaboration between numerous teams with complementary expertise. Beyond the essential stages of fundamental research, the early phases of drug discovery include, among other things, the search for bioactive chemical compounds, which generally involves a small team of five to six chemists and biologists.  In the case of the RAF project, this initial stage required the synthesis and biological evaluation of more than 900 new molecules before we were able to identify the chemical family of our candidate molecule. The next step, which was to optimize this series to design and identify a candidate that met all the criteria for a drug, including demonstrated therapeutic efficacy in vivo, required the study of more than 950 additional new molecules. This colossal task involved the commitment of more than 20 researchers, research agents, intellectual property experts, employees of external scientific service companies, and many others.

MT: My dearest wish is that this molecule will one day help save lives. IRIC's fundamental mission is to make a real difference in the fight against cancer. If the ongoing clinical trials prove conclusive and lead to the marketing of an effective drug, prescribed to patients to improve their life expectancy and quality of life, we will then be able to proudly say: mission accomplished! Beyond the clinical impact, such a success would also have significant institutional benefits for IRIC and UdeM, both in terms of visibility and financial returns.

A. M.: I would like our academic community at UdeM to fully appreciate this achievement in the academic world, accomplished with extremely limited funds, which are nowhere near the budgets of the pharmaceutical industry. I would like our community to be proud of the depth of the fundamental research conducted by UdeM researchers and the quality of the translational research being developed on our campuses.

M. T.: I am confident about the future, but also realistic. Developing a drug is like an extreme sport: it is a long, unpredictable journey fraught with obstacles. Each hurdle along the way must be overcome with rigour and resilience. I am driven by the deep conviction that one day, thanks to science, the ingenuity of the people involved and the power of teamwork, we will cross the finish line. And at the end of the road, a real cancer drug will change the lives of patients.