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Combination potentiator ('co-potentiator') therapy for CF caused by CFTR mutants, including N1303K, that are poorly
Puay-Wah Phuan1, Jung-Ho Son2, Joseph-Anthony Tan1
1Department of Medicine, University of California, San Francisco, CA 94143-0521, USA; Department of Physiology, University of California, San Francisco, CA 94143-0521, USA.
Background:
Current modulator therapies for some cystic fibrosis-causing CFTR mutants, including N1303K, have limited efficacy. We provide evidence here to support combination potentiator (co-potentiator) therapy for mutant CFTRs that are poorly responsive to single potentiators.
Methods:
Functional synergy screens done on N1303K and W1282X CFTR, in which small molecules were tested with VX-770, identified arylsulfonamide-pyrrolopyridine, phenoxy-benzimidazole and flavone co-potentiators.
Results:
A previously identified arylsulfonamide-pyrrolopyridine co-potentiator (ASP-11) added with VX-770 increased N1303K-CFTR current 7-fold more than VX-770 alone. ASP-11 increased by ~65% of the current of G551D-CFTR compared to VX-770, was additive with VX-770 on F508del-CFTR, and activated wild-type CFTR in the absence of a cAMP agonist. ASP-11 efficacy with VX-770 was demonstrated in primary CF human airway cell cultures having N1303K, W1282X and G551D CFTR mutations. Structure-activity studies on 11 synthesized ASP-11 analogs produced compounds with EC50 down to 0.5 μM.
Conclusions:
These studies support combination potentiator therapy for CF caused by some CFTR mutations that are not effectively treated by single potentiators.
Insights
Combination potentiator therapy shows promise for cystic fibrosis (CF) patients with CFTR mutations poorly responsive to single potentiators. New co-potentiators, like ASP-11, significantly enhance CFTR function in cell models.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Current cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies exhibit limited efficacy for specific CFTR mutations like N1303K.
- Certain CFTR mutants are poorly responsive to single potentiator treatments, necessitating alternative therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of combination potentiator therapy for CFTR mutants with limited response to single potentiators.
- To identify and characterize novel co-potentiators for enhancing mutant CFTR function.
Main Methods:
- Functional synergy screens were performed on N1303K and W1282X CFTR mutants using VX-770 in combination with various small molecules.
- Arylsulfonamide-pyrrolopyridine (ASP-11), phenoxy-benzimidazole, and flavone co-potentiators were identified.
- Structure-activity relationship studies were conducted on synthesized ASP-11 analogs.
Main Results:
- The arylsulfonamide-pyrrolopyridine co-potentiator ASP-11, combined with VX-770, increased N1303K-CFTR current sevenfold compared to VX-770 alone.
- ASP-11 demonstrated significant potentiation of G551D-CFTR and additive effects with VX-770 on F508del-CFTR.
- ASP-11 also activated wild-type CFTR independently of cAMP agonists, with EC50 values down to 0.5 μM for its analogs.
Conclusions:
- Combination potentiator therapy is a viable strategy for treating cystic fibrosis caused by specific CFTR mutations.
- Novel co-potentiators, such as ASP-11, offer enhanced therapeutic potential for CFTR mutants unresponsive to existing single potentiator treatments.