Modulators of anion channels and transporters as alternative therapeutic agents to normalize airway surface liquid in cystic fibrosis

Abstract

Cystic fibrosis (CF) is characterized by impaired chloride and bicarbonate secretion due to mutations in the CFTR gene which codes for a plasma membrane anion channel. Defective anion transport in CF is particularly severe in the respiratory system, with impairment of mucociliary clearance, mucus accumulation, and airway obstruction. Pharmacological CFTR modulators, able to rescue mutant CFTR trafficking and gating, have improved the clinical condition of many CF patients, particularly those with F508del mutation. However, there is a substantial number of patients with mutations unresponsive to CFTR modulators. This unmet need has prompted the exploration of alternative therapies to target the basic defect in CF. This review provides a comprehensive overview covering the years 2010-2025 of most prominent advances in the identification of small-molecule inhibitors and activators targeting three potential contributors to airway epithelium ion homeostasis: pendrin (SLC26A4), SLC26A9, and TMEM16A (ANO1). These molecules may represent potential therapeutic agents and/or be important tools of research to understand the pathophysiological role of their target. For pendrin, high-throughput screening yielded novel classes of potent and selective inhibitors including tetrahydropyrazolopyridines and pyrazolo-thiophenesulfonamides. SAR analysis led to the discovery of lead compounds PDSinh-A01 and PDSinh-C01 showing significant activity and favourable drug-like properties. Additionally, 5-benzyloxy-2-methylbenzofuran compounds have emerged as promising candidates with increased activity and favourable drug-like properties. Though SLC26A9 involvement in chloride secretion remains debated, the identification of the potent and selective inhibitor S9-A13 revealed the role of this transporter in ASL pH regulation via bicarbonate modulation. Pharmacological potentiation of TMEM16A, a calcium activated chloride channel, could be a way to bypass the defective anion transport in CF. To achieve this goal, the ETX001 compound was identified and progressed to clinical trials. TMEM16A inhibitors, such as MONNA, Ani9, and 2-acylaminocycloalkylthiophene derivatives, have been also identified and represent tools of research to assess the role of TMEM16A in different organs and tissues. Overall, the efforts towards the development of modulators of alternative ion channels and transporters opens new avenues for improving mucociliary clearance in CF.