In this project, researchers proceeded applying a ligand-based strategy in order to enlighten the most relevant chemical groups involved in the modulator ability of CFTR-F508del defect. They collected all the corrector chemo-types already known in the literature and used this set of molecules to perform pharmacophore analysis and QSAR studies. The main objectives were to identify new compounds, belonging both to the family of aminoarylthiazoles (AATs) and of VX-809 analogs. Novel AAT analogs have been designed by filtering on the information obtained by these QSAR analyses, then synthesized and tested on CFBE41o- cells expressing F508del to further explore the chemical space around the thiazole ring. In an attempt to construct more active molecules, it was thought to generate chemically hybrid compounds, blending a portion of VX809 merged to the thiazole scaffold. These AAT-VX-809 hybrid derivatives were tested in functional and biochemical assays showing a promising corrector activity. Starting from the most active compounds, a second series of hybrids that could improve the good results obtained was designed. Such molecules may represent lead compounds for the development of drugs that correct the basic F508del defect in CF patients.

Congress abstracts

– Righetti G, Liessi N, Pesce E et al. “Computational approaches for the design and chemical synthesis of novel F508del correctors in the treatment of cystic fibrosis” IX Giornate Italo-Francesi di Chimica, Genova, 16-18 aprile 2018
– Righetti G, Liessi N, Pesce E et al. “Scouting the mechanism of action of VX-809 and other F508del-CFTR correctors chemo-types by computational methods” European School of Medicinal Chemistry ESMEC, July, 1-5, 2018, Urbino, Italy