Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors. (February 2018)

• Record Type: Journal Article
• Authors: Giuliano, Kenneth A.; Wachi, Shinichiro; Drew, Lawrence; Dukovski, Danijela; Green, Olivia; Bastos, Cecilia; Cullen, Matthew D.; Hauck, Sheila; Tait, Bradley D.; Munoz, Benito; Lee, Po-Shun; Miller, John Preston
• Is Part Of: SLAS discovery. Volume 23:Number 2(2018)
• Page Start: 111
• Page End: 121
• Publication Date: 2018-02
• Subjects: amplifiers -- high-throughput screening -- CFTR modulator -- PTI-CH -- phenotypic assays; Drugs -- Analysis -- Periodicals; Drugs -- Testing -- Periodicals; Biomolecules -- Analysis -- Periodicals; Biomolecules -- Analysis; Drugs -- Analysis; Drugs -- Testing; Drug Evaluation, Preclinical; Molecular Biology -- methods; Periodicals; Periodicals; 615.1
• DOI: 10.1177/2472555217729790
• Languages: English
• ISSNs: 2472-5552

Abstract

Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54, 000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH–mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum–associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.