Validation of TMEM16A Modulation as a Therapeutic Approach for the Treatment of Cystic Fibrosis: The Discovery of Novel TMEM16A Potentiators

The discovery of transmembrane member 16A (TMEM16A) as the molecular identity of Ca 2+-activated Cl− channels (CaCCs) has reignited interest in the modulation of these channels as a therapeutic approach for the treatment of muco-obstructive respiratory diseases, including cystic fibrosis. However, the recent literature is paradoxical with some investigators suggesting that inhibition of TMEM16A is the correct approach, while others advocate increasing (potentiating) the channels activity. The lack of effective pharmacological tools has contributed to this lack of clarity on which modality will deliver benefit. In this chapter we describe the discovery of a novel tool compound (ET002663), which effectively potentiates the activity of TMEM16A, and the studies undertaken to validate the concept of enhancing TMEM16A activity as a novel approach for the treatment of cystic fibrosis.