Related Experiment Video
Updated: Dec 12, 2025
Forskolin-induced Swelling in Intestinal Organoids: An In Vitro Assay for Assessing Drug Response in Cystic Fibrosis Patients
Published on: February 11, 2017
Synthesis and biological evaluation of thiazole derivatives on basic defects underlying cystic fibrosis
Emanuela Pesce1, Nicoletta Pedemonte1, Alberto Leoni2
1U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy.
Abstract:
Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity, proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector activity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these derivatives obey Lipinski's rule of five and are expected to be orally bioavailable. Therefore, these molecules may represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity and a good pharmacokinetic profile.
Insights
Researchers explored new thiazole compounds to treat cystic fibrosis (CF). While none corrected defects, two compounds (10 and 11) enhanced the function of the faulty CFTR protein, offering a basis for future drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Genetics
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- The most common mutation, F508del-CFTR, impairs protein function through gating and processing defects.
- Thiazole-based small molecules have shown promise as dual modulators of F508del-CFTR.
Purpose of the Study:
- To design and synthesize novel thiazole derivatives as potential modulators of F508del-CFTR.
- To evaluate the corrector and potentiator activities of these new compounds.
- To identify structural features associated with F508del-CFTR potentiator activity.
Main Methods:
- Synthesis of sixteen novel thiazole derivatives.
- In vitro assessment of compounds for F508del-CFTR corrector and potentiator activity.
- In silico ADME (Absorption, Distribution, Metabolism, and Excretion) studies.
Main Results:
- None of the synthesized thiazole derivatives demonstrated significant corrector activity.
- Compounds 10 and 11 exhibited notable potentiator effects on F508del-CFTR.
- In silico analysis indicated that compounds 10 and 11 adhere to Lipinski's rule of five, suggesting good oral bioavailability.
Conclusions:
- Novel thiazole derivatives were synthesized and evaluated for F508del-CFTR modulation.
- Compounds 10 and 11 show potential as CFTR potentiators, providing insights into structure-activity relationships.
- These compounds represent promising starting points for developing improved CFTR potentiators with favorable pharmacokinetic profiles for cystic fibrosis treatment.
Related Concept Videos
01:23Cystic Fibrosis: Pathogenesis
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
01:24Cystic Fibrosis: Management
Sinus disease and chronic...