Iolanda Micco, Head of Discovery and Chemistry at Axxam, delivered a presentation which reconsidered the concept of druggability. Micco began by using the metaphor of an apple tree to illustrate the biotech industry's evolution. She explained that, like picking apples from the bottom of a tree, the industry initially tackled easier targets, leaving the more challenging, undruggable targets for later.
Micco defined undruggable targets as those for which there was no clear method of access, due to factors such as unreachable cavities, shallow binding pockets, or unknown protein structures. She highlighted the division between conservative and innovative scientists, noting that successful stories often shifted the balance towards innovation.
Advancements in science have indeed made the human proteome more accessible. However, Micco noted that despite those advancements, 80% of human proteins remain intractable. She emphasised the need for game-changers in the field, citing examples such as pharmacological chaperones, protein degraders, and covalent inhibitors. Successful stories like Tafamidis, Lumacaftor, and the first KRAS inhibitor demonstrated the potential of these approaches.
Micco then focused on Axxam's approach, which integrated biology and chemistry to tackle undruggable targets. She described the evolution of biological assays, from phenotypical assays to more advanced techniques measuring transcriptional activity, RNA splicing, and protein degradation. In chemistry, Axxam expanded its chemical space with natural compounds, PROTACs, RNA splicing modulators, and covalent binders.
Micco highlighted the use of machine learning to design libraries of protein-protein interaction inhibitors and covalent binders. She mentioned Axxam's collaboration with Symeres to develop a platform for preparing and screening PROTACs. Micco concluded by emphasising the need to embrace new challenges and break traditional rules to advance the field.
