- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Multicenter Surveillance of Cystic Fibrosis in Korean Children. (Pubmed Central) - Sep 30, 2022
Early diagnosis and treatment availability may improve outcomes. CFTR modulators may be effective for Asian patients with rare CFTR mutations, c.1322T>C (p.Leu441Pro).
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Cystic fibrosis transmembrane regulator correction attenuates heart failure-induced lung inflammation. (Pubmed Central) - Aug 17, 2022
In a mouse model of HF, pharmacological CFTR corrector therapy (Lumacaftor (Lum)) was applied systemically or lung-specifically for 2 weeks, and the lungs were analyzed using histology, flow cytometry, western blotting, and qPCR...Collectively, our data suggest that downregulation of CFTR in the HF lung extends to non-alveolar macrophages with consequences for tissue inflammation and vascular structure. Pharmacological CFTR correction possesses the capacity to alleviate HF-associated lung inflammation.
- |||||||||| lumacaftor (VX-809) / Vertex
DUBTAC: The development of a new modality for protein stabilization (W182 (McCormick Place Convention Center)) - Aug 9, 2022 - Abstract #ACSFall2022ACS_Fall_644;
Using chemoproteomic approaches, we discovered the covalent ligand that critically targets a non-catalytic allosteric cysteine and we will describe a DUBTAC consisting of our DUB-recruiter linked to lumacaftor (a drug that binds ΔF508-cystic fibrosis transmembrane conductance regulator), that robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We will also describe chemistry and data supporting this modality as we showcase how covalent chemoproteomic approaches enabled the development of a new induced proximity-based therapeutic modalities.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Genome-wide functional genomics analyses of F508del-CFTR degradation (Ballroom A) - Aug 5, 2022 - Abstract #NACFC2022NACFC_433;
Our platform provides uswith a launching point for double-knockout and gene –drug CRKO screens to identify novel gene–gene and gene–drug interactions. We hope to build a comprehensive model for F508del-CFTR ERAD that can inform the nextgeneration of CF therapeutics.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex
Impacts of elexacaftor/tezacaftor/ivacaftor on days of antibiotic treatment in people living with cystic fibrosis (120 AB) - Aug 5, 2022 - Abstract #NACFC2022NACFC_420;
ELX/TEZ/IVA is effective in significantly reducing days ofantibiotic therapy in PwCF, including those with advanced lung disease. Itis a widely efficacious and beneficial treatment for PwCF.688 Lipid-based therapeutic strategies in addition to cystic fibrosistransmembrane conductance regulator modulators for cystic fibrosistreatment
- |||||||||| elexacaftor (VX-445) / Vertex, Kalydeco (ivacaftor) / Vertex, tezacaftor (VX-661) / Vertex
Preclinical, Journal: Net benefit of ivacaftor during prolonged tezacaftor/elexacaftor exposure in vitro. (Pubmed Central) - Jul 29, 2022
These results demonstrate that ivacaftor is a critical component in the triple combination therapy along with tezacaftor and elexacaftor to increase constitutive CFTR function. This work further elucidates the mechanism of action of the effective triple combination therapeutic that is now the primary clinical tool in treating CF.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: In Silico Screening of Novel TMPRSS2 Inhibitors for Treatment of COVID-19. (Pubmed Central) - Jul 17, 2022
We think that lumacaftor and ergotamine, which we screened through in silico studies, can effectively inhibit the activity of TMPRSS2. Our findings provide a basis for subsequent in vitro experiments, having important implications for the development of effective anti-COVID-19 drugs.
- |||||||||| Journal: Molecular Dynamics and Theratyping in Airway and Gut Organoids Reveal R352Q-CFTR Conductance Defect. (Pubmed Central) - Jul 9, 2022
The combination approach of in vitro patient-derived cell models and in silico MD simulations to characterize rare CFTR mutations can improve the specificity and sensitivity of modulator response predictions and aid in their translational use for CF precision medicine. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, cystic fibrosis therapeutic / Cyclenium
Journal: Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR. (Pubmed Central) - Jul 2, 2022
This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Primary Human Nasal Epithelial Cells: Biobanking in the Context of Precision Medicine. (Pubmed Central) - May 17, 2022
Triple therapy VX-445 + VX-661 + VX-770 significantly increased correction of CFTR activity compared to dual therapy VX-809 + VX-770. The measure of CFTR activity in HNE cells is a promising pre-clinical biomarker useful to guide CFTR modulator therapy.
- |||||||||| Trikafta (elexacaftor/tezacaftor/ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Review, Journal: Small-molecule drugs for cystic fibrosis: Where are we now? (Pubmed Central) - May 6, 2022
This paper aims to give an up-to-date overview of old and novel CFTR modulators as well as of novel strategies based on small-molecule drugs. Further investigations in in-vivo and cell-based models as well as carrying out large prospective studies will be required to determine if novel CFTR modulators, stabilizers, amplifiers, and the ENaC inhibitors or TMEM16A potentiators will further improve the clinical outcomes in CF management.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Deubiquitinase-targeting chimeras for targeted protein stabilization. (Pubmed Central) - Apr 27, 2022
We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS.
- |||||||||| elexacaftor (VX-445) / Vertex, lumacaftor (VX-809) / Vertex
Journal: Highway to Cell: Selection of the Best Cell-Penetrating Peptide to Internalize the CFTR-Stabilizing iCAL36 Peptide. (Pubmed Central) - Apr 24, 2022
More importantly, using this TatRI-iCAL36 peptide, we were able to reveal for the first time an additive increase in the CFTR amount in the presence of VX-445/VX-809 compared to VX-445/VX-809 treatment alone. This finding is a significant contribution to the development of CFTR-stabilizing peptides in addition to currently used treatments (small-molecule correctors or potentiators) for CF patients.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Structural Comparative Modeling of Multi-Domain F508del CFTR. (Pubmed Central) - Apr 23, 2022
Furthermore, we modeled F508del/R1070W and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809 on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs that target F508del CFTR for treatment of CF.
- |||||||||| Characterisation of F508del-CFTR rescue by corrector PTI-801 (ePoster Corner) - Apr 14, 2022 - Abstract #ECFS2022ECFS_520;
PTI-801 demonstrated additivity to the genetic revertants G550E, R1070W and 4RK, but was unable to rescue DD/AA trafficking. In summary, these preliminary findings suggest that PTI-801 acts as a pharmacological chaperone and may have different binding sites compared to other correctors, namely VX-661, VX-809, ABBV-2222 and FDL-169.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays. (Pubmed Central) - Mar 27, 2022
This study is aimed (i) at identifying three molecules (9b, 9g, and 9j), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Epigenome editing of the CFTR-locus for treatment of cystic fibrosis. (Pubmed Central) - Mar 3, 2022
Here, we demonstrate that therapeutic interventions that increase the expression of CFTR may improve the efficacy of CFTR modulators. A better understanding CFTR regulatory mechanisms could uncover novel therapeutic interventions for the development of cystic fibrosis therapies.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Mechanism of CFTR correction by type I folding correctors. (Pubmed Central) - Feb 23, 2022
Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: The Mitochondrial Ca import complex is altered in ADPKD. (Pubmed Central) - Feb 1, 2022
We conclude that enhanced Ca signaling and alterations in proteins association with the mitochondrial Ca uptake complex are associated with malfunction of PC1. Finally, our results identify novel therapeutic targets for treating ADPKD.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis. (Pubmed Central) - Jan 19, 2022
We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809...Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Probing Allosteric Hsp70 Inhibitors by Molecular Modelling Studies to Expedite the Development of Novel Combined F508del CFTR Modulators. (Pubmed Central) - Dec 29, 2021
Their effectiveness as CFTR modulators has been verified by biological assays, in combination with VX-809, whose positive results confirmed the reliability of the whole applied computational method. Along with this, the "in-silico" prediction of absorption, distribution, metabolism, and excretion (ADME) properties highlighted, once more, that AATs may represent a chemical class to be further investigated for the rational design of novel combination of compounds for CF treatment.
- |||||||||| lumacaftor (VX-809) / Vertex, Symproic (naldemedine) / Shionogi, BDSI, Promacta (eltrombopag) / Novartis
Biomarker, Journal: Bioinformatics Identification of Ferroptosis-Related Biomarkers and Therapeutic Compounds in Ischemic Stroke. (Pubmed Central) - Oct 30, 2021
Several potential therapeutic compounds corresponding to MAP1LC3B, PTGS2, and TLR4 were also identified for ischemic stroke, including Zinc12503187 (Conivaptan), Zinc3932831 (Avodart), Zinc64033452 (Lumacaftor), Zinc11679756 (Eltrombopag), Zinc100378061 (Naldemedine), and Zinc3978005 (Dihydroergotamine). Our results suggested MAP1LC3B, PTGS2, and TLR4 as potential diagnostic biomarkers for ischemic stroke, providing more evidence about the vital role of ferroptosis in ischemic stroke.
- |||||||||| lumacaftor (VX-809) / Vertex
[VIRTUAL] Efficient generation of fully differentiated and functional human airway organoids () - Oct 19, 2021 - Abstract #NACFCI2021NACFC_I_1105;
In some experiments, organoid cultures were treated with CFTR corrector VX-809 for 24 hours, and then amiloride, forskolin, and genistein were added for 6 hours to induce organoid swelling. In summary, the PneumaCult Airway Organoid Kit supports efficient generation of fully differentiated, functional human airway organoids and provides an alternative method of in vitro modeling of the human airway that does not require porous culture insert
- |||||||||| elexacaftor (VX-445) / Vertex, lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
[VIRTUAL] Development of an iPSC-based toolbox to study cystic fibrosis () - Oct 19, 2021 - Abstract #NACFCI2021NACFC_I_1079;
This platform holds significant potential for development of novel therapeutics for less-common CFTR mutations, such as the Class 1 nonsense mutations. Further work should focus on comparing iPSC derived AECs with their primary HBEC counterparts in terms of reproducibility, scalability, and fidelity to in-vivo clinical drug efficacy
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