lumacaftor (VX-809) / Vertex - LARVOL DELTA

CFTR correctors suppress Ca²⁺-cAMP signaling and cyst growth in primary cultures of ARPKD cholangiocytes. (PubMed, Cell Calcium) - "These changes were accompanied by profound remodeling of intracellular signaling, including elevated resting cytosolic Ca²⁺, an increased thapsigargin-releasable endoplasmic reticulum Ca²⁺ pool, increased STIM1 expression, reduced IP₃ receptor expression, a marked increase in intracellular cAMP, and a switch in adenylyl cyclase isoform expression characterized by increased AC3 and reduced AC6...Treatment with either VX-809 or VX-445 improved many of these abnormalities by increasing CFTR expression, partially restoring PC1 and PC2 expression, attenuating abnormal Ca²⁺ and cAMP signaling, reducing cholangiocyte proliferation and cyst growth, and shifting CFTR membrane distribution toward the WT pattern...These findings identify coordinated remodeling of Ca²⁺- and cAMP-dependent signaling as a central feature of ARPKD cholangiocytes and show that CFTR correctors are associated with improvement of multiple disease-associated pathways. Our results support..."

Journal • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Nephrology • Polycystic Kidney Disease • Pulmonary Disease • Renal Disease • Respiratory Diseases • CFTR • PKD1 • PKHD1 • STIM1

Targeting trafficking defects in long QT syndrome type 2: a phase 2 clinical study with patient-specific cellular validation. (PubMed, Eur Heart J) - "Short-term LUM therapy is safe and yields a significant QTc shortening in LQT2 patients with a trafficking defect. Concordance between cellular and clinical findings reinforces the value of a mechanism-based, variant-informed approach and supports the feasibility of trafficking-correction strategies within a precision-medicine framework for inherited arrhythmia syndromes."

Journal • P2 data • Cardiovascular • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • KCNH2

Implications of a basolateral-to-apical Cl− gradient on CFTR Cl− ion transport in two primary human airway cell models (NACFC 2026) - " In both PALI- and VALI-differentiated hBE cultures treated with tezacaftor (TEZ), lumacaftor (LUM), or elexacaftor/tezacaftor (ELX/TEZ), Cl− gradient conditions enhanced CFTR function. Use of a Cl− gradient expanded the CFTR Cl− transport assay window in both PALI- and VALI-differentiated hBE cultures, with a more pronounced effect in PALI cultures. CFTR function was similarly enhanced in PALI-S–differentiated non-CF small airway cultures, supporting applicability to distal airway models. While PALI differentiation yields more in vivo–like epithelial morphology, incorporation of a Cl− gradient may improve assay sensitivity for CFTR functional studies."

Gene Therapies • Pulmonary Disease • Respiratory Diseases

Targeted ribosomal subunit depletion sensitizes elexacaftorresistant P67L CFTR to correction (NACFC 2026) - "However, P67L-CFTR is responsive to drugs that bind early to the nascent peptide (Tezacaftor/Lumacaftor), which synergistically improve folding and trafficking when used alongside VX-445. This study distinguishes the pro-folding benefits of targeted ribosomal stress from global ribosome velocity deceleration. By utilizing the fast-misfolding P67L-CFTR variant as a translational biosensor, we uncouple generalized biogenesis surveillance from specific, protective chaperone recruitment. This work aims to provide a novel biological framework for how altered translation environments can temporarily stabilize nascent peptides, revealing how endogenous cellular networks can naturally mimic the structural stabilization provided by early-binding pharmacological therapies."

Computational Identification of Potential HMG-CoA Reductase Modulators Through Drug Repurposing: Structural Insights and Therapeutic Implications. (PubMed, Curr Comput Aided Drug Des) - "The study identifies computationally prioritized candidate scaffolds for putative non-orthosteric HMGCR modulation and defines the biochemical, kinetic, and structural validation required before any therapeutic interpretation."

Journal • Dyslipidemia • Metabolic Disorders

Single-cell analysis of the synovium and infrapatellar fat pad identifies key pathogenic genes and drug targets in osteoarthritis. (PubMed, Int J Clin Exp Pathol) - "This study identified the key cell populations driving OA progression in the synovium and IFP, and screened four novel diagnostic biomarkers and three potential drug targets for OA, with their expression verified in an in vitro OA model. Lumacaftor and naldemedine were found to have multi-target binding activity to OA core drug targets. These findings deepen the understanding of OA's molecular mechanisms mediated by the synovium and IFP, and provide valuable experimental evidence for OA's early diagnosis and the development of targeted therapeutic drugs, including old drug repurposing."

Journal • Immunology • Metabolic Disorders • Osteoarthritis • Pain • Rheumatology • IL15 • IR • PTGDS

TAB2 Causes Neuronal Damage by Aggravating Microglia-Mediated Neuroinflammation in Parkinson's Disease. (PubMed, Adv Sci (Weinh)) - "We further showed that the FDA-approved drug, lumacaftor, suppressed microglial TAB2 expression and had potent anti-inflammatory and neuroprotective effects in PD models. Taken together, our study reveals that the STAT3-TAB2-NF-κB-IL-1β positive feedback axis in microglia is a crucial checkpoint that exacerbates neuroinflammation in PD. Therefore, these findings identify a pivotal role of TAB2 in regulating microglia-mediated neuroinflammation, suggesting that targeting TAB2 may be a possible therapeutic strategy for PD."

Journal • CNS Disorders • Inflammation • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • Targeted Protein Degradation • IL1B • STAT3

The PON1-NDUFA4 axis maintains mitochondrial respiratory fitness and drives lenvatinib tolerance in hepatocellular carcinoma. (PubMed, Mol Cancer Res) - "Structure-guided virtual screening identified the Food and Drug Administration-approved CFTR corrector lumacaftor as a potent modulator of PON1 that disrupted the PON1-NDUFA4 interaction and enhanced the antitumor efficacy of lenvatinib in vivo. Targeting mitochondrial protein-stabilizing mechanisms such as PON1-NDUFA4 may offer a broadly applicable strategy for overcoming therapy resistance in liver cancer and other aggressive malignancies. Implications: These findings establish mitochondrial protein stabilization as an actionable therapeutic vulnerability and provide a rationale for combination strategies to overcome targeted therapy resistance in HCC."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • PON1

Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases. (PubMed, Isr J Chem) - "VX-770, a CFTR potentiator, and CFTR correctors like VX-809, VX-661, and VX-445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Proteinopathy • Pulmonary Disease • Respiratory Diseases • CFTR

Repurposing FDA-Approved Drugs as Potential Inhibitors of Feline Infectious Peritonitis Virus 3CLpro: An Integrated In Silico and In Vitro Study with Synergistic Combination Analysis. (PubMed, ACS Pharmacol Transl Sci) - "Synergy analysis with established anti-FIP agents (GC376, remdesivir, GS-441524, and molnupiravir) using SynergyFinder 3.0 revealed strong synergistic interactions: saquinavir + GC376 (mean ZIP score: 54.59), lumacaftor + GC376 (mean ZIP: 21.44), and gliquidone + remdesivir (mean ZIP: 24.13). These rational combinations enable substantial dose reduction, offering practical strategies to improve treatment accessibility, reduce costs, and minimize adverse effects. This study establishes a framework for repurposing FDA-approved drugs in FIP therapy and supports translational evaluation of these combination regimens."

FDA event • Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • IFNB1 • IL6 • TNFA

NAALADL1 modulates cellular resistance to Tumor Treating Fields in colorectal cancer. (PubMed, NPJ Precis Oncol) - "Virtual screening further identified Lumacaftor and Bestatin as candidate NAALADL1 inhibitors, which synergized with TTFields to suppress CRC cell growth. These findings highlight significant heterogeneity in CRC cell line responses to TTFields and identify NAALADL1 as a key modulator of resistance, suggesting its potential as a target for improving TTFields-based therapies in CRC."

Journal • Brain Cancer • Colorectal Cancer • Glioblastoma • Oncology • Solid Tumor • FOLH1

The Ion Channel, CFTR, assembles with HIPPO pathway proteins TAZ and YAP in polycystic kidney disease. (PubMed, J Biol Chem) - "We show that both TAZ and YAP are increased in the nuclei of untreated RC kidneys as compared to normal kidneys. Importantly, VX-809 reduces TAZ and YAP in the nucleus to levels comparable to those in normal kidneys, providing mechanistic insight into how CFTR modulator therapy reduces proliferation."

Journal • Autosomal Dominant Polycystic Kidney Disease • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease

Targeting von Willebrand factor selectively under inflammatory conditions. (PubMed, bioRxiv) - "The results indicate that lumacaftor may indeed have the desired properties of inhibiting VWF selectively when oxidized. Because of its simplicity, the assay provides a high-throughput method to efficiently screen multiple drugs against VWF in both its oxidized and unoxidized state."

Journal • Inflammation • Thrombosis

CFTR modulator monotherapy for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). (PubMed, Cochrane Database Syst Rev) - "There is a lack of evidence to support monotherapy with a CFTR modulator for pwCF who have two F508del variants (F508del/F508del)."

Clinical • Journal • Monotherapy • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Structure-based virtual screening identifies VX-809 as a candidate dual-pathway modulator in fuchs endothelial corneal dystrophy. (PubMed, Sci Rep) - "Together, these findings show that structure-based screening can reveal previously unrecognized multi-target activities in existing drugs and identify candidate modulators of converging pathogenic pathways in FECD. This study provides proof of concept for docking-based polypharmacology strategies to accelerate early-stage discovery for multifactorial ocular diseases."

Journal • Ophthalmology • Transplantation • ATF6 • TGFB1

Comparative and subtractive genomics reveals novel therapeutic targets in cystic fibrosis-associated multidrug-resistant Pandoraea sputorum. (PubMed, Diagn Microbiol Infect Dis) - "Notably, lumacaftor is a drug currently used in cystic fibrosis therapy. This study provides a comprehensive genome-guided framework for understanding P. sputorum and identifying therapeutic opportunities. The identified drug targets and repurposed candidates offer promising avenues for combating multidrug-resistant P. sputorum infections, particularly in CF and immunocompromised patients."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases

Lighting up the linear ubiquitin code: a bioluminescent sensor for M1-specific deubiquitinase activity and drug discovery. (PubMed, Chem Commun (Camb)) - "This high-throughput assay identified baicalein and lumacaftor as novel OTULIN inhibitors from an FDA-approved compound library, validated by STD-NMR and cellular assays. The reporter enables drug discovery targeting linear ubiquitin signaling without specialized synthesis."

Journal • Targeted Protein Degradation

Discovery of novel repurposed anthelminthics against Trichinella spiralis and albendazole-resistant nematodes through metabolomics-guided virtual screening. (PubMed, Curr Res Parasitol Vector Borne Dis) - "Lumacaftor, entrectinib, and fluspirilene showed the lowest binding energies and were tested in vitro. Importantly, entrectinib also killed both ABZ-sensitive and ABZ-resistant Caenorhabditis elegans at lower concentrations than ABZ, demonstrating potent activity against resistant nematodes. Our findings suggest that entrectinib is a promising candidate for a novel anthelmintic, with potential to overcome ABZ resistance in trichinellosis and other parasitic infections."

Journal • Infectious Disease • Metabolic Disorders • Musculoskeletal Pain • Pain

Breast cancer tumor immune microenvironment landscape identifies prognostic risk genes and potential drugs. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "Furthermore, fourteen candidate drugs targeting this network were predicted, and structural analogs of Lumacaftor and Ivosidenib showed promising docking affinities to CD1C and CXCR3, respectively. These findings provide preliminary insights into TIM-associated prognostic pathways and suggest candidate compounds for further investigation in BRCA."

Journal • Breast Cancer • Oncology • Solid Tumor • BRCA • CD1C • CD40LG • CD69 • CXCR3

Trikafta restores thermodynamic coupling between two nucleotide binding domains for potentiating CFTR activity. (PubMed, Biomed Pharmacother) - "While folding correctors VX-445 and VX-809 are sufficient to rescue its folding and thermal defects by restoring Mg/ATP mediated dimerization between the two nucleotide binding domains (NBD1 and NBD2), the thermodynamic basis for the precise activity potentiation by VX-770 in Trikafta remains unknown. The results demonstrated that comparable thermostability between dimerized NBD1 and NBD2 was required to stabilize an activated intermediate for the channel activity potentiation by VX-770. Thus, tight coupling between dimerized NBD1 and NBD2 upon a global induced fit across the interdomain interfaces is still required for Trikafta modulators to rescue the gating defect of the F508del mutant."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Lumacaftor and fexofenadine prevent donepezil-induced LQTS via PHE656-mediated hERG chaperoning. (PubMed, Biochem Pharmacol) - "FEX and LUM significantly antagonized DPZ-induced prolongation of the QT interval and APD90. Collectively, FEX and LUM effectively prevent DPZ-induced cardiotoxicity by competitively binding to the hERG PHE656 site and repairing the Hsp70/Hsp90 chaperone system, offering a novel therapeutic strategy for clinical management of drug-induced LQTS."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • CDC37 • HSP90AA1

Inflammatory response in CF airway epithelial cells: a comparative study of modulators and wild-type CFTR rescue. (PubMed, Front Pharmacol) - "The combination of pharmacological modulators such as lumacaftor, tezacaftor, and elexacaftor restore CFTR activity at the plasma membrane and improve lung function in patients carrying CFTR mutations such as F508del, their effects on inflammation are less clear. These findings suggest that beyond ion transport, the proper folding and structural integrity of CFTR are important for regulating inflammation, potentially through interactions with other cellular proteins involved in inflammatory pathways. This work highlights the need to develop therapeutic strategies that not only restore chloride channel function but also fully correct CFTR misfolding to better control inflammation in CF."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR

Exploration of the protein and pharmacological landscape of monkeypox virus treatment: from entry point to end point. (PubMed, Mol Divers) - "Current therapeutics, such as tecovirimat (targeting VP37 to block egress), brincidofovir, and cidofovir (inhibiting DNA polymerase E9L), offer symptomatic relief but face hurdles like resistance mutations (e.g., A314V in E9L) and suboptimal efficacy in immunocompromised patients...Computational approaches integrating AI-driven screening, molecular dynamics simulations, and multi-omics have pinpointed repurposed candidates like lumacaftor and conivaptan as VP37 inhibitors. This integrative framework advocates for combination therapies, personalized regimens based on clade profiling, and global collaboration to mitigate MPXV's adaptive potential. By bridging virology and pharmacology, the review charts pathways for innovative drug development to combat this zoonotic threat effectively."

IO biomarker • Journal • Review • Infectious Disease

Barriers to the Pharmacologic Rescue of W1282X CFTR. (PubMed, Biochemistry) - "Additionally, acute in vitro treatments with approved modulators VX-809 or VX-661 result in immediate potentiation of W1282X-dependent ion transport, showing that F508del CFTR correctors also augment W1282X CFTR channel activity...Clinically approved CFTR correctors VX-445, VX-121, and VX-809 elicited potentiation of G551D CFTR...Moreover, unlike other CFTR mutations such as F508del, proteasome blockade using ALLN partially rescues W1282X at the plasma membrane. These results highlight ways in which detailed mechanistic analysis and modulator profiling are needed to characterize CFTR mutations such as W1282X and that modulator function in rare variants can be quite distinct from classical findings based strictly upon F508del CFTR."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions. (PubMed, Eur Respir J) - "We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected in vivo Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA