A Novel 7H-[1,2,4]Triazolo[3,4-b]thiadiazine-based Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Directed toward Treatment of Cystic Fibrosis

• Type of Material: Article
• Authors: Andras Rab, Emory University; Xun Yang, Emory University; Will Tracy, Emory University; Jeong Hong, Emory University; Disha Joshi, Emory University; Candela Manfredi, Emory University; Sadhana S. Ponnaluri, Emory University; Alexander Kolykhalov, Emory University; Min Qui, Emory University; Haian Fu, Emory University; Yuhong Du, Emory University; Huw Davies, Emory University; Eric J. Sorscher, Emory University
• Language: English
• Date: 2023-09-20
• Publisher: American Chemical Scoeity
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1021/acsmedchemlett.3c00155
• Title of Journal or Parent Work: ACS Medicinal Chemistry Letters
• Volume: 14
• Issue: 10
• Start Page: 1338
• End Page: 1343
• Grant/Funding Information: This study was supported by Cystic Fibrosis Foundation (SORSCH21XX0 grant) and the Wish For Wendy Foundation (0000035045 award).
• Keywords: high throughput compound library screening; cystic fibrosis; drug discovery; CFTR
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology

Abstract

Cystic fibrosis (CF) is an autosomal genetic disorder caused by disrupted anion transport in epithelial cells lining tissues in the human airways and digestive system. While cystic fibrosis transmembrane conductance regulator (CFTR) modulator compounds have provided transformative improvement in CF respiratory function, certain patients exhibit marginal clinical benefit or detrimental effects or have a form of the disease not approved or unlikely to respond using CFTR modulation. We tested hit compounds from a 300,000-drug screen for their ability to augment CFTR transepithelial transport alone or in combination with the FDA-approved CFTR potentiator ivacaftor (VX-770). A subsequent SAR campaign led us to a class of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines that in combination with VX-770 rescued function of G551D mutant CFTR channels to approximately 400% above the activity of VX-770 alone and to nearly wild-type CFTR levels in the same Fischer rat thyroid model system.