134 Rationale for evaluating (R)-roscovitine (Seliciclib) in patients with cystic fibrosis

Objectives (R)-Roscovitine, an inhibitor of cyclin-dependent kinases, is currently under clinical evaluation as a drug candidate against various cancers, Cushing disease and rheumatoid arthritis. Roscovitine has diverse biological properties that could be potentially beneficial in the treatment of CF. Results 1Roscovitine acts as a proteostasis regulator that corrects the trafficking of ΔF508-CFTR. 2Roscovitine improves the bactericidal properties of macrophages from CF patients, by affecting the TRPC6 calcium channel (independently of the CFTR mutation) and by lowering the intraphagolysosomal pH that is abnormally elevated in CF macrophages. 3Its main metabolite also shows a ΔF508-CFTR ‘corrector' effect and biological activity on macrophages, despite lack of kinase inhibitory effects. 4Roscovitine has an anti-inflammatory effect likely originating from its ability to promote neutrophil apoptosis. 5Roscovitine reduces eosinophil degranulation and promotes apoptosis. 6Roscovitine suppresses CD4+ T helper cells differentiation into Th17 (pro-inflammatory lymphocytes) and promotes their differentiation into Tregs (anti-inflammatory lymphocytes). 7Roscovitine is an orally available drug which has undergone preclinical pharmacological and toxicological studies, extensive phase I and II clinical trials, in particular against lung cancer. Conclusion Altogether these data suggest that repurposing roscovitine for CF is a therapeutically and economically valid proposal. We will present the first clinical protocol designed to validate safety and potential beneficial effects of roscovitine in CF patients with chronic lung Pseudomonas aeruginosa infection.