1. Constrained Bithiazoles: Small Molecule Correctors of Defective ΔF508–CFTR Protein Trafficking
- Author
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Choong L. Yoo, Baoxue Yang, Brandi M. Hudson, Mark J. Kurth, Gui J. Yu, Huy Nguyen, Dean J. Tantillo, Alan S. Verkman, Michael W. Lodewyk, Puay Wah Phuan, Deanna Montgomery, Alex L. Bagdasarian, and Keith C. Coffman
- Subjects
Mutant ,Thyroid Gland ,Cystic Fibrosis Transmembrane Conductance Regulator ,Plasma protein binding ,Article ,Cyclooctanes ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Animals ,Humans ,Cycloheptanes ,ΔF508 ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Epithelial Cells ,Small molecule ,In vitro ,Cystic fibrosis transmembrane conductance regulator ,Rats ,Cell biology ,Ring size ,Protein Transport ,Thiazoles ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Molecular Medicine ,Protein trafficking - Abstract
Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
- Published
- 2014