AR-001 Opens Airways by Dampening Calcium Signaling

Lung disease states are exacerbated by excessive TMEM16 signaling

Identified in 2008 as the key ion channel that controls calcium flux in the airways and is required for airway smooth muscle contraction1,2
Pharmacologic inhibition3 or genetic deletion4 of TMEM16 leads to profound reduction of both airway tightening & mucus secretion5,6
TMEM16 inhibitors also block TGF-β mediated fibrosis7, and infection by airway viruses8,9 which is a major trigger of asthma exacerbations
  1. Cell. 2008 Sep 19;134(6): 1019-29.
  2. Science. 2008 Oct 24; 322(5901): 590-4.
  1. Am J Physiol Lung Cell Mol Physiol. 2013 Nov 1; 305(9): L625-34.4. J
  2. FASEB J. 2019 Mar; 33(3): 4 502-4512.
  3. S. Jeon et al. (2020) Antimicrob Agents Chemother 64
  4. Int J Mol Sci. 2021 Jul 22;22(15): 7852
  1. S. Jeon et al. (2020) Antimicrob Agents Chemother 64
  2. Antimicrob Agents Chemother. 2020, Jun 23; 64(7): e00819
  3. Nature 2021 Jun;594(7861): 88-93

Niclosamide Identified as a Potent TMEM16A Inhibitor From a Large Target Based Screen

Nanomolar potency in cell assay;
more potent than benchmark compounds
Niclosamide is top TMEM16A hit
(only approved drug in top hits)
Structure of niclosamide bound to TMEM16A

Y. Cheng et al. (2022) Res Sq doi: 10.21203/rs.3.rs-1296933/v1 [image shown: internal molecular docking studies of niclosamide binding site on TMEM16A]

Learn more about AR-001 effect on the asthma cascade

Niclosamide Fully Relaxes Airways When β-agonists Don't

β-agonists

Niclosamide

Fully Relaxed Airway

Suboptimal Relaxation

AR-001 Works in the Presence of Inflammation

All data from: K. Miner et al. (2019) Frontiers Pharmacol. 10(51), 1-34

AR-001 Works in the Presence of High Contractiles (Carbachol, CCh)