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. Anesthesiology. 2015 Sep;123(3):569-81
  2. J Allergy Climun Imnol. 2018 Apr; 141(4):1259
  3. Am J Respir Cell Mol Biol. 2021 Jan;64(1):50-58
  4. Int J Mol Sci. 2021 Jul 22;22(15):7852
  1. Am J Physiol Lung Cell Mol Physiol. 2024 Jan 1;326(1):L111
  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

K. Miner et al., J.K. Sullivan (2019) Frontiers Pharmacol. 10(51), 1-34
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)

TMEM16A inhibition offers the first new MOA in 100 years to relax airway smooth muscle tightening

  • Calcium influx triggered by multiple contractile signals is essential for bronchoconstriction
  • TMEM16A mediates depolarization that triggers robust calcium entry
  • Blocking calcium entry blocks contraction to bronchodilate airways
  • Unlike the β-agonists, TMEM16A blockade is not compromised by over-use or inflammation

TMEM16A signals promote epithelial mucus production

  1. F.Huang et al. (2012) ProcNatl Acad Sci U S A 109, 16354-16359.
  2. P. Scudieri etal. (2012) J Physiol 590,6141-6155.
  3. K. Miner et al. (2019) Frontiers inPharmacology 10, 51.
  4. R. Benedetto et al. (2019) FASEB J 33,4502-4512.
  5. I.Cabrita et al. (2019) JCI Insight 4.
  6. I. Cabrita et al. (2021) Am J Respir CellMol Biol 64, 50-58
  • Steroid treatment of asthma & COPD doesn’t block mucus
  • TMEM16A activation leads to mucin production and secretion
  • Inflammation induces higher TMEM16A expression required for mucin production1-6
  • AR-001 blocks both contraction and mucus secretion in an asthma model5
  1. F.Huang et al. (2012) ProcNatl Acad Sci U S A 109, 16354-16359.
  2. P. Scudieri etal. (2012) J Physiol 590,6141-6155.
  3. K. Miner et al. (2019) Frontiers inPharmacology 10, 51.
  4. R. Benedetto et al. (2019) FASEB J 33,4502-4512.
  5. I.Cabrita et al. (2019) JCI Insight 4.
  6. I. Cabrita et al. (2021) Am J Respir CellMol Biol 64, 50-58