The only approved potentiator drug for gating mutations, VX-770, provides significant, albeit partial, restoration of the channel function for the most common gating mutant, G551D-CFTR, while partially inhibits the long-term lung function decay. Several rare gating mutations are marginally responsive to the VX-770 activation but, based on published and preliminary data, we posit that the function of several gating mutants could be improved by the synergistic action of VX-770 with preclinical gating potentiators. Thus, there is an unmet need to 1) improve the pharmacotherapy efficacy of the most common CF gating mutations, and 2) identify novel pharmacophore scaffolds that, either alone or in combination, can maximally rescue the activity of resistant CFTR variants. Towards these goals, we recently identified a molecular scaffold as a versatile starting point for the development of novel CFTR potentiators. Screening of our in-house synthesized small molecule library led to the selection of a hit compound (K014X), capable of improving the G551D-CFTR function to a significantly higher level than VX-770 (unpublished, submitted).
Moreover, the additivity of K014X in combination with VX-770 suggests that K014X have a distinct mechanism of action and binding site relative to that of VX-770. Based on these preliminary results, our project has the aim to produce and test novel K014X derivatives to improve functional rescue efficacy of VX-770-resistant common and rare CFTR mutations. We will focus on the determination of the structure-activity relationship and combinatorial profiling in association with VX-770 and other available preclinical CFTR potentiators.
Considering the anticipated complementary mechanism of action of these potentiators in relation to VX-770 and VX-445, the proposed research will pave the way for the development of a novel polypharmacology approach that will allow more effective therapy for CF patients carrying (ultra-) rare CFTR gating mutations that are poorly responsive to VX-770.
Contacts: Adriana Chilin (email: adriana.chilin@unipd.it)