- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex
[VIRTUAL] Chronic cAMP-dependent stimulation results in less activation of elexacaftor/tezacaftor/ivacaftor-corrected F508del CFTR () - Oct 19, 2021 - Abstract #NACFCI2021NACFC_I_1065;
Continuation of this work is underway, with plans for replication of experiments and examination of colocalization of B2AR, adenosine, and VIP receptors, with CFTR by immunofluorescence and evaluation of the effect of chronic B2AR agonist exposure on VIP/adenosine-stimulated CFTR function. An ongoing secondary aim of the investigation is to characterize the in vivo effect of chronic B2AR agonist exposure on CFTR activation in healthy subjects measured by nasal potential difference testing in a randomized, double blind, placebo-controlled, crossover trial.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: DNAJB12 and Hsp70 Triage Arrested Intermediates of N1303K-CFTR for ER Associated-Autophagy. (Pubmed Central) - Sep 17, 2021
N1303K-CFTR is excluded from the ER-exit sites, and its passage from the ER to autolysosomes does not require ER-phagy receptors. DNAJB12 operates in biosynthetically active ER-microdomains to triage membrane protein intermediates in a conformation-specific manner for secretion versus degradation via ERAD or selective-ER-associated autophagy.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: The CFTR P67L variant reveals a key role for N-terminal lasso helices in channel folding, maturation, and pharmacologic rescue. (Pubmed Central) - Aug 22, 2021
Based on limited proteolysis, pulse chase, and molecular dynamics analysis of full-length CFTR and a series of deletion constructs, we argue that P67L and other maturational processing (class 2) defects impair the integrity of the lasso motif and confer misfolding of downstream domains. Thus, amino terminal missense variants elicit a conformational change throughout CFTR that abrogates maturation while providing a robust substrate for pharmacologic repair.
- |||||||||| lumacaftor (VX-809) / Vertex
Synthesis of photoaffinity labels derived from VX-809 (Room: Hall B4) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_4875;
Three final reactions install an alkyne pull-down tag and form the aryl azide photoaffinity label. The successful synthesis of these PALs will enable investigation of the VX-809 CFTR binding site.
- |||||||||| lumacaftor (VX-809) / Vertex
Lessons learned from use of the 1,2,3-triazole as an amide bioisostere in cystic fibrosis drugs VX-809 and VX-770 (Room: Hall B4) - Aug 13, 2021 - Abstract #ACSFall2021ACS_Fall_3970;
These studies revealed subtle spatial and electronic differences between the amide and 1,2,3-triazole analogs. The lessons learned in the context of the cystic fibrosis drugs VX-809 and VX-770 could help inform medicinal chemists considering the use of the 1,2,3-triazole bioisostere.Structural comparison of the positional and electronic features of the amide and 1,2,3-triazole bioisosteres.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype. (Pubmed Central) - Jul 4, 2021
Further validation in CFTR knock-out mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by using CFTR modulators VX770-VX809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.
- |||||||||| Journal: Partial Rescue of F508del-CFTR Stability and Trafficking Defects by Double Corrector Treatment. (Pubmed Central) - Jul 4, 2021
We found that VX-445, particularly in combination with type I (VX-809, VX-661) and type II (corr-4a) correctors, elicits a large rescue of F508del-CFTR function...Despite this high efficacy, analysis of ubiquitylation, resistance to thermoaggregation, protein half-life, and subcellular localization revealed that corrector combinations did not fully normalize F508del-CFTR behavior. Our study indicates that it is still possible to further improve mutant CFTR rescue with the development of corrector combinations having maximal effects on mutant CFTR structural and functional properties.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays. (Pubmed Central) - May 27, 2021
To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
[VIRTUAL] Linking CFTR modulators to Pseudomonas aeruginosa infection (Track 1) - May 10, 2021 - Abstract #ECFS2021ECFS_230;
Differently, ivacaftor synergised with colistin and polymyxin at low concentrations (1-4 µg/ml) on almost all bacterial isolates...Furthermore, P. aeruginosa infection impacts ivacaftor concentration and exposure, potentially affecting its activity. Overall, these data suggest a complex interaction among CFTR modulators, P. aeruginosa infection and antibiotics.
- |||||||||| Symdeko (tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, bamocaftor (VX-659) / Vertex
Preclinical, Journal: Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies. (Pubmed Central) - Apr 17, 2021
Thus, the airway inflammatory milieu from late- and early-stage CF lung disease improves the efficacy of CFTR modulators, regardless of the combination therapy used. Our findings suggest that pre-clinical evaluation of CFTR corrector therapies should be performed under conditions mimicking the native inflammatory status of CF airways, and altering the inflammatory status of CF airways may change the efficacy of CFTR modulator therapies.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Molecular Docking and QSAR Studies as Computational Tools Exploring the Rescue Ability of F508del CFTR Correctors. (Pubmed Central) - Mar 30, 2021
Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2, an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability...This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.
- |||||||||| elexacaftor (VX-445) / Vertex, lumacaftor (VX-809) / Vertex
[VIRTUAL] iPSC Derived Airway Epithelial Cells Recapitulate Key Aspects of CFTR Biology () - Mar 14, 2021 - Abstract #ATS2021ATS_5020;
Conclusions iPSC-derived airway epithelium recapitulates key aspects of CFTR biology in both 3D and air-liquid interface cultures. These scalable patient-specific assays, offer opportunities to advance drug discovery for currently undertreated CF patients.
- |||||||||| lumacaftor (VX-809) / Vertex, GLPG1837 / AbbVie
Journal: Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR. (Pubmed Central) - Feb 16, 2021
For G542X- and E60X-CFTR, the only mechanism capable of generating functional proteins is the read-through, but the outcome of read-through products is highly variable depending on the interplay between the missense mutation caused by the read-through and the structural context of the protein. Pharmacological studies of these three PTCs with various CFTR modulators suggest position-dependent therapeutic strategies for these disease-inflicting mutations.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Phenotyping of Rare CFTR Mutations Reveals Distinct Trafficking and Functional Defects. (Pubmed Central) - Feb 13, 2021
We investigated four rare CFTR mutations E60K, G85E, E92K and A455E against well-characterized mutations, F508del and G551D, and their responses to corrector VX-809 and/or potentiator VX-770...Conclusions. Since no single model or assay allows deciphering all defects at once, we propose a combination of phenotypic assays to collect rapid and early insights into the multiple defects of CFTR variants.
- |||||||||| Symdeko (tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Journal: The Extra-pulmonary Effects of CFTR Modulators in Cystic Fibrosis. (Pubmed Central) - Jan 26, 2021
Based on an even smaller number of studies evaluating the extra-pulmonary effects of lumacaftor-ivacaftor (LUM-IVA), the benefits are less clear. While limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extra-pulmonary manifestations of CF.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Characterization of the Mechanism of Action of RDR01752, a Novel Corrector of F508del-CFTR. (Pubmed Central) - Jan 12, 2021
The lack of additivity of RDR01752 with the genetic revertant R1070W suggests that this compound has the same effect as the insertion of tryptophan at 1070, i.e., filling the pocket at the NBD1:ICL4 interface in F508del-CFTR, similarly to VX-809. Combination of RDR01752 with correctors mimicking the rescue by revertants G550E or 4RK could thus maximize rescue of F508del-CFTR.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Clinical, Journal: Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A > G. (Pubmed Central) - Dec 16, 2020
Although the mechanism of acute inhibition of channel activity of rescued DF508 CFTR of VX-809 is yet to be fully elucidated, the markedly less pronounced inhibition observed by the experimental CFTR modulator J1.12 shows promising potential as further experiments shed more light on this finding. This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Correctors modify the bicarbonate permeability of F508del-CFTR. (Pubmed Central) - Dec 2, 2020
Interestingly, the permeability of bicarbonate increases in the cells containing corrected p.F508del CFTR channels is greater than the increase of the halide permeability. These different increases of the permeability of bicarbonate and halides are consistent with the concept that the structural conformation of the pore of the corrector-rescued p.F508del channels would be different than the normal wild type CFTR protein.
- |||||||||| Arina-1 (inhaled bicarbonate/glutathione/ascorbic acid) / Renovion
Journal: Novel Therapy of Bicarbonate, Glutathione and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport. (Pubmed Central) - Oct 21, 2020
This response was absent in CFBE41o- F508del cells treated with VX-809 and primary HBE cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on CF mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in CF.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Combination of Selective PARP3 and PARP16 Inhibitory Analogues of Latonduine A Corrects F508del-CFTR Trafficking. (Pubmed Central) - Oct 19, 2020
At 1 or 10 μM, neither 5 or 6 alone showed F508del-CFTR corrector activity, but when added together at 1 or 10 μM each, the combination exhibited F508del-CFTR corrector activity identical to 1 or 10 μM latonduine A (1), respectively, supporting its novel dual PARP target mechanism of action. Latonduine A (1) showed additive in vitro corrector activity in combination with the clinically approved corrector VX809, making it a potential new partner for cystic fibrosis combination drug therapies.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Lumacaftor-rescued F508del-CFTR has a modified bicarbonate permeability. (Pubmed Central) - Oct 16, 2020
This difference would indicate a diverse conformation of the rescued F508del-CFTR, that is plausibly reflected on an improper regulation of the airway surface liquid, lessening the efficacy of the corrector. Our findings rather support the idea that a combination of correctors would be required to address the CFTR-dependent bicarbonate permeability.
- |||||||||| lumacaftor (VX-809) / Vertex
[VIRTUAL] EFFICIENT GENERATION OF FULLY DIFFERENTIATED AND FUNCTIONAL HUMAN AIRWAY ORGANOIDS () - Oct 7, 2020 - Abstract #NACFC2020NACFC_804;
In some experiments, the cultures were treated with 10 M of the CFTR corrector VX-809 for 24 hours, and then 10 M forskolin was added for an additional 3 hours to induce organoid swelling...In summary, PneumaCult™ Airway Organoid Kit is a novel serum-free medium that can efficiently generate fully differentiated and functional human airway organoids. This culture technique provides an alternative method for in vitro human airway modeling that does not require cell culture inserts, thus facilitating high-throughput drug screening.
- |||||||||| lumacaftor (VX-809) / Vertex
[VIRTUAL] A NATIONAL RESOURCE CENTER TO ADVANCE NASAL CELL THERATYPING IN CF () - Oct 7, 2020 - Abstract #NACFC2020NACFC_801;
For subjects with rare CFTR variants and their care teams, the center provides a nationally accessible resource for individual theratyping that has been highly effective in supporting insurance approval requests for appropriate coverage. For the greater research community, this platform will provide the necessary numbers to assess the fidelity and resolution of nasal cell models to predict clinical outcomes in subjects with rare variants.
- |||||||||| lumacaftor (VX-809) / Vertex
[VIRTUAL] IDENTIFICATION OF CFTR PROTEOSTASIS PROFILES REGULATING PHARMACOLOGIC RESCUE OF PROTEIN MISFOLDING MUTATIONS () - Oct 7, 2020 - Abstract #NACFC2020NACFC_503;
Furthermore, we identify that mutations exhibiting robust lumacaftor response may have varied levels of correction among other types of small-molecule correctors, particularly those currently used in clinical combination therapy among more diverse patient groups. The relative difference in CFTR interactome remodeling in response to such mutations and treatments may indicate ways in which certain mutations such as P67L are primed as more susceptible substrates for lumacaftor correction while also identifying mechanisms that limit the rescue for other variants, such as G85E.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
[VIRTUAL] EXPLORING THE RESPONSE OF CFTR TRAFFICKING MUTANTS TO CORRECTORS () - Oct 7, 2020 - Abstract #NACFC2020NACFC_494;
These results confirm the critical role of NBD1 (where I507del and R560S are located), ICL4 (where H1079P occurs) and TM11 (where Q1100P occurs) for the folding of CFTR. Furthermore, the results also show that, although sharing the same cellular phenotype (absence of mature form) and thus requiring the same therapeutic strategy (a corrector compound), class II mutations induce distinct molecular defects that cannot be rescued by the same correctors, namely currently approved ones, thus requiring further drug discovery initiatives.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
[VIRTUAL] FUNCTIONAL RESCUE OF CFTR VARIANTS INCLUDING W1282X IN PRIMARY HBE CELLS BY CFTR MODULATORS () - Oct 7, 2020 - Abstract #NACFC2020NACFC_482;
These data are consistent with clinical observations for CFTR F508del and provide evidence that CF patients carrying the W1282X nonsense mutation could benefit from combinations of approved CFTR modulators with readthrough/NMD targeting therapies. Functional rescue of variant CFTR by Vertex modulator drugs in passage 2 primary hBE cells (AUC/min in A/cm2)* * Treatment was for 48 h; **triple = elexacaftor/tezacaftor/ivacaftor
- |||||||||| lumacaftor (VX-809) / Vertex
[VIRTUAL] PHARMACOLOGICAL DEPLETION OF ERF1 OR ERF3A ENHANCES EFFECT OF AMINOGLYCOSIDES ON CFTR PREMATURE TERMINATION CODON READTHROUGH () - Oct 7, 2020 - Abstract #NACFC2020NACFC_476;
To enhance expression and function of CFTR protein resulting from readthrough, TR modulators are often combined with a NMD inhibitor (eg, SMG1i) and a CFTR corrector (eg, VX-809)...A combination treatment may also allow a dose reduction of TR modulator drugs and thus lessen toxicity concerns that exist for most readthrough drugs. Finally, these compounds represent valuable tools to further investigate the therapeutic potential of other TR reagents and to understand the basic mechanism of translation termination.
- |||||||||| lumacaftor (VX-809) / Vertex, Alverix (amiloride hydrochloride) / Remedica
[VIRTUAL] HYPERGLYCEMIC CONDITIONS DYSREGULATE BARRIER AND CHANNEL FUNCTION IN HUMAN CYSTIC FIBROSIS BRONCHIAL EPITHELIA () - Oct 7, 2020 - Abstract #NACFC2020NACFC_441;
Surprisingly, the TER of 16HBE-F508del cells on Transwells decreased through time when cultured in normal (5.5 mM) glucose, which was not rescued by 24-hour incubation with 3 M VX-809...In both HBE-WT and HBE-F508del cells, amiloride-sensitive epithelial sodium channel (ENaC) currents were significantly decreased, and calcium-activated K+ (BK) channel currents were significantly increased...Furthermore, primary HBE-F508del cells are much more sensitive to high glucose than HBE-WT cells which may directly contribute to lung dysfunction, particularly in the context of CFRD. (Support: Marcus Professorship in CF, NIH F31 HL143863-01.)
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