Identification of GLPG/ABBV-2737, a Novel Class of Corrector, Which Exerts Functional Synergy With Other CFTR Modulators.

Gert De Wilde,Ashvani K Singh,Katja Conrath,Anne-Sophie Wesse,Luc Nelles,Marlon Cowart,Tzyh-Chang Hwang,Steven Van Der Plas,Thierry Christophe,Nicolas Desroy,Mia Jans,Sara Musch,Maarten Gees,Katleen Verdonck,Pieter Stouten,Mathieu Pizzonero

doi:10.3389/fphar.2019.00514

Abstract

The deletion of phenylalanine at position 508 (F508del) in cystic fibrosis transmembrane conductance regulator (CFTR) causes a severe defect in folding and trafficking of the chloride channel resulting in its absence at the plasma membrane of epithelial cells leading to cystic fibrosis. Progress in the understanding of the disease increased over the past decades and led to the awareness that combinations of mechanistically different CFTR modulators are required to obtain meaningful clinical benefit. Today, there remains an unmet need for identification and development of more effective CFTR modulator combinations to improve existing therapies for patients carrying the F508del mutation. Here, we describe the identification of a novel F508del corrector using functional assays. We provide experimental evidence that the clinical candidate GLPG/ABBV-2737 represents a novel class of corrector exerting activity both on its own and in combination with VX809 or GLPG/ABBV-2222.

Highlights

Cystic fibrosis (CF) is a life-threatening, recessive genetic disease caused by mutations in a gene on chromosome 7 encoding for the CFTR protein
The CSE-HRP system used CFBE41O-cells, a lung epithelial cell line, stably transfected with F508del CFTR tagged with HRP in the fourth extracellular loop (Veit et al, 2014)
The CSEMEM system, used U2OS cells, an osteosarcoma epithelial cell line, stably transfected with F508del CFTR tagged with a Prolink moiety at the C-terminal and a plasma membrane located EA moiety

Summary

Introduction

Cystic fibrosis (CF) is a life-threatening, recessive genetic disease caused by mutations in a gene on chromosome 7 encoding for the CFTR protein. The CFTR protein is a cyclic adenosine monophosphate (cAMP)-regulated anion channel expressed primarily at the apical plasma membrane of secretory epithelia, and is responsible for the homeostasis of salt and water content on epithelial surfaces (Lubamba et al, 2012). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction causes the hallmark electrolyte elevation in sweat, and thick and viscous secretions affecting the lungs, reproductive tract and most exocrine glands, notably the pancreas, intestine, and bile duct. Frontiers in Pharmacology | www.frontiersin.org de Wilde et al. Identification of GLPG/ABBV-2737, a Novel CFTR Corrector in pulmonary function (O’Sullivan and Freedman, 2009; Lubamba et al, 2012; Okiyoneda et al, 2013; Pittman and Ferkol, 2015)

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Results

Conclusion