@article {Singhjpet.119.261800, author = {Ashvani K Singh and Yihong Fan and Corina Balut and Sara Alani and Arlene Manelli and Andrew M Swensen and Ying Jia and Torben R Neelands and Timothy A Vortherms and Bo Liu and Xenia B Searle and Xueqing Wang and Wenqing Gao and Tzyh-Chang Hwang and Hongyu Ren and Douglas Cyr and Philip R Kym and Katja Conrath and Chris Tse}, title = {Biological characterization of F508delCFTR protein processing by the CFTR Corrector ABBV-2222/GLPG2222}, elocation-id = {jpet.119.261800}, year = {2019}, doi = {10.1124/jpet.119.261800}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Cystic Fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e. F508del mutation) in CF, two biomolecular activities are required, namely correctors to increase the {\textquotedblleft}amount{\textquotedblright} of properly folded F508delCFTR levels at the cell surface, and potentiators to allow the effective opening, i.e. {\textquotedblleft}function{\textquotedblright} of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary "triple combination" therapy consisting of two corrector molecules, type 1 (C1) and type 2 (C2) with additive mechanisms along with a potentiator (P) are being investigated in the clinic for maximum restoration of mutated CFTR function (Hongyu et al., 2017). We report the identification and in vitro biological characterization of ABBV-2222/GLPG2222, a novel, potent and orally bioavailable C1 corrector developed by Abbvie-Galapagos, and currently in clinical trials that exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug-interaction (DDI) compared to VX-809 (herein reported as Lumacaftor) and improvements in potency and efficacy compared to VX-661 (herein reported as Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 \<10 nM.SIGNIFICANCE STATEMENT To address the most prevalent defect of the defective CFTR protein (i.e. F508del mutation) in Cystic Fibrosis, Abbvie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and is currently in clinical trials that exhibits substantial improvements over the existing C1 correctors.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2019/11/15/jpet.119.261800}, eprint = {https://jpet.aspetjournals.org/content/early/2019/11/15/jpet.119.261800.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }