CFTR (Cystic fibrosis transmembrane conductance regulator) is a member of the ATP-Binding Cassette Transporter superfamily (ABCC7). And the CFTR exists in many cell types throughout the body, but in the airways it exists mainly in secretory serous cells of the submucosal glands. CFTR works as a channel for small anions, such as chloride and bicarbonate. CFTR’s domain architecture includes two transmembrane domains, two nucleotide binding domains (NBDs), and a regulatory R-region. Phosphorylation of CFTR cytosolic R domain, and ATP binding and hydrolysis at NBDs can regulate CFTR activity. Importantly, dysregulation of CFTR function can lead to life-threatening diseases such as secretory diarrhoea and cystic fibrosis.

Cystic Fibrosis (CF) is the most common life-shortening genetic disease among Caucasians, resulting from mutations in the gene encoding the CFTR. CF affects more than 70,000 individuals worldwide. Interestingly, the entirety of CFTR is sensitive to mutation, with some 2000 genetic variants having been described. However, F508del-CFTR is by far the most common variant, with a ~70% allele frequency in U.S. patients. For a subset of these mutations, small-molecule therapeutics exists that increase the activity of CFTR. The first FDA-approved drug, VX-770, is a gating potentiator that helps certain CFTR mutants conduct more chloride upon activation by sub-maximal phosphorylation. The second drug, VX-809, is a trafficking corrector that helps certain CFTR mutants reach the cell membrane. Today, we will introduce a CFTR channel potentiator, Icenticaftor (QBW251).

Icenticaftor is a potent and orally active potentiator of CFTR channel.

Specifically, Icenticaftor can restore CFTR function in specific CFTR genotypes as well as wild-type CFTR. Icenticaftor has anti-chronic obstructive pulmonary disease (COPD) and CF activities. COPD is a progressive lung disease characterized by persistent airflow obstruction. Meanwhile, Icenticaftor could improve sweat chloride and pulmonary function in individuals with particular CFTR mutations localized to the cell surface. Besides, Icenticaftor exhibits high oral bioavailability (90%) in Sprague-Dawley rats. Icenticaftor is safe and well tolerated in vivo.

To sum up, Icenticaftor is an orally active CFTR channel potentiator. And it is a potent compound of COPD and cystic fibrosis research.

References：

[1]. Sawada A, et, al. Development. 2005 Nov;132(21):4719-29.