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Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways

Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, View ORCID ProfileKarl Kunzelmann, View ORCID ProfileDeanna Mohn, View ORCID ProfileAndreas Hochheimer, View ORCID ProfileJohn K. Sullivan
doi: https://doi.org/10.1101/254888
Kent Miner
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Katja Labitzke
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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Benxian Liu
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Paul Wang
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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Kathryn Henckels
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Kevin Gaida
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Robin Elliott
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Jian Jeffrey Chen
3Department of Medicinal Chemistry, Amgen Inc., Thousand Oaks, CA, USA
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Longbin Liu
3Department of Medicinal Chemistry, Amgen Inc., Thousand Oaks, CA, USA
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Anh Leith
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Esther Trueblood
4Department of Comparative Biology and Safety Sciences, Amgen Inc., Seattle, WA, Thousand Oaks, CA and South San Francisco, CA, USA
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Kelly Hensley
4Department of Comparative Biology and Safety Sciences, Amgen Inc., Seattle, WA, Thousand Oaks, CA and South San Francisco, CA, USA
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Xing-Zhong Xia
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Oliver Homann
5Genome Analysis Unit, Amgen Inc., South San Francisco, CA, USA
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Brian Bennett
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Mike Fiorino
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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John Whoriskey
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Gang Yu
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Sabine Escobar
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Min Wong
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Teresa L. Born
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Alison Budelsky
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Mike Comeau
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Dirk Smith
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Jonathan Phillips
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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James A. Johnston
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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Joe McGivern
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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Kerstin Weikl
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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David Powers
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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Karl Kunzelmann
6Institut für Physiologie, Universität Regensburg, Regensburg, Germany
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  • ORCID record for Karl Kunzelmann
Deanna Mohn
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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  • ORCID record for Deanna Mohn
  • For correspondence: jksullivan@polestarbio.com andreas.hochheimer@isarbioscience.de dmohn@amgen.com
Andreas Hochheimer
2Department of Therapeutic Discovery, Amgen Inc., Thousand Oaks, CA, USA and Regensburg, Germany
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  • ORCID record for Andreas Hochheimer
  • For correspondence: jksullivan@polestarbio.com andreas.hochheimer@isarbioscience.de dmohn@amgen.com
John K. Sullivan
1Department of Inflammation Research, Amgen Inc., Thousand Oaks, CA and Seattle, WA, USA
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  • ORCID record for John K. Sullivan
  • For correspondence: jksullivan@polestarbio.com andreas.hochheimer@isarbioscience.de dmohn@amgen.com
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Abstract

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated-Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted November 14, 2018.
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Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, Karl Kunzelmann, Deanna Mohn, Andreas Hochheimer, John K. Sullivan
bioRxiv 254888; doi: https://doi.org/10.1101/254888
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Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
Kent Miner, Katja Labitzke, Benxian Liu, Paul Wang, Kathryn Henckels, Kevin Gaida, Robin Elliott, Jian Jeffrey Chen, Longbin Liu, Anh Leith, Esther Trueblood, Kelly Hensley, Xing-Zhong Xia, Oliver Homann, Brian Bennett, Mike Fiorino, John Whoriskey, Gang Yu, Sabine Escobar, Min Wong, Teresa L. Born, Alison Budelsky, Mike Comeau, Dirk Smith, Jonathan Phillips, James A. Johnston, Joe McGivern, Kerstin Weikl, David Powers, Karl Kunzelmann, Deanna Mohn, Andreas Hochheimer, John K. Sullivan
bioRxiv 254888; doi: https://doi.org/10.1101/254888

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