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


Ion Channels as Targets in Drug Discovery (eds. Gary Stephens, Edward Stevens)


Henry Danahay, Martin Gosling



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


Keywords: Q2 2024

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