Identification and Characterization of Novel CFTR Potentiators

Abstract

There is still a high unmet need for the treatment of most patients with cystic fibrosis (CF). The identification and development of new Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators is necessary to achieve higher clinical benefit in patients. In this report we describe the characterization of novel potentiators. From a small screening campaign on F508del CFTR, hits were developed leading to the identification of pre-clinical candidates GLPG1837 and GLPG2451, each derived from a distinct chemical series. Both drug candidates enhance WT CFTR activity as well as low temperature or corrector rescued F508del CFTR, and are able to improve channel activity on a series of Class III, IV CFTR mutants. The observed activities in YFP halide assays translated well to primary cells derived from CF lungs when measured using Trans-epithelial clamp circuit (TECC). Both potentiators improve F508del CFTR channel opening in a similar manner, increasing the open time and reducing the closed time of the channel. When evaluating the potentiators in a chronic setting on corrected F508del CFTR, no reduction of channel activity in presence of potentiator was observed. The current work identifies and characterizes novel CFTR potentiators GLPG1837 and GLPG2451, which may offer new therapeutic options for CF patients.

CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

“…ABBV-974 and ABBV-2451 have demonstrated greater and similar CFTR potentiation, respectively, in comparison with ivacaftor in R117H-, G178R-, S549N-, and G551D-expressing cells (Gees et al, 2018;Van der Plas et al, 2018). Interestingly, the simultaneous administration of ABBV-974 or ABBV-2451 with ivacaftor did not further enhance CFTR function, indicating that these molecules may act by the same mechanism of action (Yeh et al, 2017;Van der Plas et al, 2018).…”

“…Several novel potentiators have demonstrated promising effects and are currently under experimental and clinical investigations (Phuan et al, 2015;Park et al, 2016;Yeh et al, 2017;Gees et al, 2018). The potentiators VX-561 (deutivacaftor or formerly CTP-656; Vertex Pharmaceuticals) is a deuterated form of ivacaftor that demonstrated an enhanced stability in vitro and in healthy volunteers compared to ivacaftor (Harbeson et al, 2017), which would allow CF patients to take it once daily rather than twice as it has been the case with the ivacaftor.…”

Phenotyping of Rare CFTR Mutations Reveals Distinct Trafficking and Functional Defects

“…The assay was performed as detailed in [19]. Briefly, cells were transfected with a plasmid encoding a halide sensitive yellow fluorescent protein (YFP-H148Q/I152L/F46L) [20] using PEI (polyethylenimine) and immediately plated into black, clear-bottomed 96-well plates coated with Poly-D-Lysine.…”

Antisense oligonucleotide-mediated correction ofCFTRsplicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

“…Four days later, equivalent currents (Ieq) were measured using a TECC-24 workstation. Transepithelial voltage (Vt) and resistance (Rt) were recorded to calculate an Ieq attributable to forskolin-stimulated chloride secretion following the addition of benzamil to inhibit sodium currents mediated by epithelial sodium channels (ENaC) on the apical membrane ( Figure 2A) (49)(50)(51). We also tested the activity of the potentiator VX-770, an FDA-approved therapeutic for patients with CFTR c.3718-2477C>T (27).…”