How to determine the mechanism of action of CFTR modulator compounds: A gateway to theranostics

Abstract

The greatest challenge of 21st century biology is to fully understand mechanisms of disease to drive new approaches and medical innovation. Parallel to this is the huge biomedical endeavour of treating people through personalized medicine. Until now all CFTR modulator drugs that have entered clinical trials have been genotype-dependent. An emerging alternative is personalized/precision medicine in CF, i.e., to determine whether rare CFTR mutations respond to existing (or novel) CFTR modulator drugs by pre-assessing them directly on patient's tissues ex vivo, an approach also now termed theranostics. To administer the right drug to the right person it is essential to understand how drugs work, i.e., to know their mechanism of action (MoA), so as to predict their applicability, not just in certain mutations but also possibly in other diseases that share the same defect/defective pathway. Moreover, an understanding the MoA of a drug before it is tested in clinical trials is the logical path to drug discovery and can increase its chance for success and hence also approval. In conclusion, the most powerful approach to determine the MoA of a compound is to understand the underlying biology. Novel large datasets of intervenients in most biological processes, namely those emerging from the post-genomic era tools, are available and should be used to help in this task.

Keywords: Correctors; Cystic fibrosis; Drug targets; Pharmacology; Potentiators; Theratypes.