Treating protein folding disorders with small molecule CFTR correctors
Novel CFTR corrector compounds that are effective in rescuing halide efflux in a cell are provided. Also provided are methods for treating protein folding disorders (e.g., cystic fibrosis). The methods include administering a CFTR corrector compound or pharmaceutically acceptable salt or prodrug thereof. Methods of screening for CFTR corrector compounds are also described herein. The methods of screening include contacting a cell that endogenously expresses a CFTR mutation with the compound to be screened and detecting a rescue of halide efflux from the cell.
1. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject a CFTR corrector compound, wherein the CFTR corrector compound has the following structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, halogen, alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted alkyl; and
R 2 , R 3 , and R 4 are each independently substituted or unsubstituted alkyl.
2. The method of claim 1 , wherein the protein folding disorder is cystic fibrosis.
3. The method of claim 1 , wherein R 1 is chloro, fluoro, or methoxy.
4. The method of claim 1 , wherein R 2 is methyl.
5. The method of claim 1 , wherein R 3 is methyl.
6. The method of claim 1 , wherein R 4 is methyl or ethyl.
7. The method of claim 1 , wherein the compound is
8. The method of claim 1 , wherein the compound is
9. The method of claim 1 , wherein the compound is
10. The method of claim 1 , wherein the compound is
11. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject a CFTR corrector compound, wherein the CFTR corrector compound has the following structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 3 are independently absent or each independently selected from hydrogen or substituted or unsubstituted alkyl;
R 2 is substituted or unsubstituted amino, substituted or unsubstituted thio, or substituted or unsubstituted heterocycloalkyl; and
is a single bond or double bond, wherein two double bonds are not adjacent,
wherein optionally R 1 and R 2 are combined to form a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
12. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject a CFTR corrector compound, wherein the CFTR corrector compound has the following structure:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or substituted or unsubstituted carbonyl;
R 2 is hydrogen, carboxyl, or substituted or unsubstituted aryl;
R 3 is hydrogen, hydroxyl, trifluoromethyl, or substituted or unsubstituted alkyl; and
R 4 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.
13. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject a CFTR corrector compound, wherein the CFTR corrector compound has the following structure:
or a pharmaceutically acceptable salt thereof.
14. A method for the treatment of a protein folding disorder in a subject, comprising:
administering to the subject a CFTR corrector compound, wherein the CFTR corrector compound has the following structure:
or a pharmaceutically acceptable salt thereof.