F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review

Abstract

Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options.

Areas covered: This review covers the discovery of F508del-CFTR correctors described in both patents (2005 - present) and scientific literatures.

Expert opinion: Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening.

Keywords: cystic fibrosis; cystic fibrosis transmembrane regulator; cystic fibrosis transmembrane regulator corrector; cystic fibrosis transmembrane regulator modulator; cystic fibrosis transmembrane regulator potentiator; ivacaftor; lumacaftor.