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<p>Pharmacologic activation of the cystic fibrosis transmembrane conductance regulator (CFTR) has transformed cystic fibrosis (CF) therapy. Other, more common airway diseases can also be associated with CFTR deficiency. For example, individuals with one dysfunctional CFTR variant (i.e., CF carriers), as well as those with acquired CFTR deficiency, are predisposed to both non-CF bronchiectasis and chronic rhinosinusitis, raising the possibility that CFTR stimulation in these settings could provide clinical improvement. This study describes a new triazolo-thiadiazine-based compound series optimized to augment mutant and wildtype CFTR function when administered topically to airway epithelium. Mechanism of action appears attributable—at least in part—to phosphodiesterase 4 inhibition (PDE4i), with effects on other PDEs also noted. Together with a growing body of previous and emerging evidence, our results suggest a novel therapeutic strategy for treating people with CF (PwCF) who lack access to effective modulator therapy—and addressing common diseases such as chronic bronchiectasis and rhinosinusitis in the non-CF population.</p>

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A novel drug series optimized to address cystic fibrosis and other CFTR deficiency diseases of human airways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Andras Rab,
  • Jeong S. Hong,
  • Candela Manfredi,
  • Disha Joshi,
  • Sadhana Ponnaluri,
  • William F. Tracy,
  • Yujie Luo,
  • Xun Yang,
  • Alexander A. Kolykhalov,
  • Huw M. L. Davies,
  • Eric J. Sorscher

摘要

Pharmacologic activation of the cystic fibrosis transmembrane conductance regulator (CFTR) has transformed cystic fibrosis (CF) therapy. Other, more common airway diseases can also be associated with CFTR deficiency. For example, individuals with one dysfunctional CFTR variant (i.e., CF carriers), as well as those with acquired CFTR deficiency, are predisposed to both non-CF bronchiectasis and chronic rhinosinusitis, raising the possibility that CFTR stimulation in these settings could provide clinical improvement. This study describes a new triazolo-thiadiazine-based compound series optimized to augment mutant and wildtype CFTR function when administered topically to airway epithelium. Mechanism of action appears attributable—at least in part—to phosphodiesterase 4 inhibition (PDE4i), with effects on other PDEs also noted. Together with a growing body of previous and emerging evidence, our results suggest a novel therapeutic strategy for treating people with CF (PwCF) who lack access to effective modulator therapy—and addressing common diseases such as chronic bronchiectasis and rhinosinusitis in the non-CF population.