The main results of the project were: A)Refining cysteamine structure, since the chemical optimization of cysteamine led to a series of novel compounds (CT-family), active in restoring F508delCFTR function. In particular, CT11 is the best-optimized molecule, being able to restore CFTR function equally to cysteamine but at a lower concentration. These results were obtained via SPQ assay, in both CFBE41o- cells and ex vivo in cells collected by nasal brushing from CF patients. Moreover, CT11 was seen to restore Beclin 1-dependent autophagy and to reduce P62, decreasing at the same time the inflammation biomarkers (phospho) p42/44 MAPK. Similar effects on both CFTR rescue and autophagy were obtained in F508del-CFTR homozygous (CftrF508del\F508del) mice. B) Identification of new approved lead compounds active in restoring F508delCFTR function: a small number of approved entities were identified and prioritized for experimental validation via SPQ assay in CFBE41o- cells. Three compounds showed encouraging results: AMX, CT47 and PTE were able to restore CFTR function at a lower concentration than cysteamine. The novel compounds identified may pave the way to further studies with a combination of molecules (or a single drug candidate) to treat CFTR-F508del defect.

Pubblications

– Purzner T, Purzner J, Buckstaff T et al. “Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma” Science Signaling 2018 Sep 11;11(547). pii: eaau5147. doi: 10.1126/scisignal.aau5147