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Updated: Jun 13, 2026

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Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121.

Ashish Rajesh Jhangiani1, John A Olson2,3, Austin Tedman1

  • 1The James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University, West Lafayette, Indiana, USA.

Biorxiv : the Preprint Server for Biology
|June 12, 2026
PubMed
Summary
This summary is machine-generated.

VX-121, a cystic fibrosis (CF) therapeutic, generally improves CFTR gene expression for rare variants more than VX-445. However, one variant showed reduced response, and VX-121 avoids a key off-target interaction seen with VX-445.

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Last Updated: Jun 13, 2026

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Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients
06:14

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

Published on: October 15, 2017

Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Cystic fibrosis (CF) is a genetic disorder caused by over 1,200 variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • While common CFTR variants like F508del have targeted therapies, rare variants exhibit variable responses to existing treatments.
  • VX-121, a component of Alyftrek, presents a potential new option for rare CF variants, but its efficacy across all variants is not fully understood.

Purpose of the Study:

  • To evaluate the impact of VX-121 on the plasma membrane expression of 232 rare CFTR variants using deep mutational scanning (DMS).
  • To compare the efficacy of VX-121 against VX-445 for various rare CFTR variants.
  • To investigate the molecular mechanisms underlying VX-121's interactions with CFTR variants.

Main Methods:

  • Deep mutational scanning (DMS) to assess plasma membrane expression of 232 rare CFTR variants.
  • Computational docking to analyze protein-ligand interactions.
  • Photo-crosslinking to identify off-target interactions.

Main Results:

  • VX-121 generally enhanced CFTR variant expression more effectively than VX-445, particularly for variants in the first membrane spanning domain (MSD1).
  • The Y1032C variant demonstrated reduced response to VX-121 compared to VX-445, with computational docking suggesting altered coordination due to mutation.
  • VX-121 was shown to avoid a significant off-target interaction associated with VX-445.

Conclusions:

  • VX-121 shows broad potential for enhancing rare CFTR variant expression, offering a promising therapeutic avenue.
  • Understanding variant-specific responses and molecular interactions is crucial for optimizing CFTR modulator therapy.
  • VX-121's distinct interaction profile compared to VX-445 may offer therapeutic advantages and a better safety profile.