Ani9, a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2

Yohan Seo, Ho K. Lee, Jinhong Park, Dong Kyu Jeon, Sungwoo Jo, Minjae Jo, Wan Namkung

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Anoctamin1 (ANO1)/transmembrane protein 16A (TMEM16A), a calcium-activated chloride channel (CaCC), is involved in many physiological functions such as fluid secretion, smooth muscle contraction, nociception and cancer progression. To date, only a few ANO1 inhibitors have been described, and these have low potency and selectivity for ANO1. Here, we performed a high-throughput screening to identify highly potent and selective small molecule inhibitors of ANO1. Three novel ANO1 inhibitors were discovered from screening of 54,400 synthetic small molecules, and they were found to fully block ANO1 channel activity with an IC50 < 3 μM. Electrophysiological analysis revealed that the most potent inhibitor, 2-(4-chloro-2-methylphenoxy)-N-[(2-methoxyphenyl)methylideneamino]-acetamide (Ani9), completely inhibited ANO1 chloride current with submicromolar potency. Notably, unlike previous small-molecule ANO1 inhibitors identified to date, Ani9 displayed high selectivity for ANO1 as compared to ANO2, which shares a high amino acid homology to ANO1. In addition, Ani9 did not affect the intracellular calcium signaling and CFTR chloride channel activity. Our results suggest that Ani9 may be a useful pharmacological tool for studying ANO1 and a potential development candidate for drug therapy of cancer, hypertension, pain, diarrhea and asthma.

Original languageEnglish
Article numbere0155771
JournalPLoS One
Volume11
Issue number5
DOIs
Publication statusPublished - 2016 May 1

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chloride channels
Chloride Channels
Muscle Neoplasms
screening
nociception
Fluids and Secretions
acetamides
Molecules
neoplasms
transmembrane proteins
Nociception
Calcium Signaling
muscle contraction
Screening
asthma
Muscle Contraction
smooth muscle
hypertension
Inhibitory Concentration 50
drug therapy

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Seo, Yohan ; Lee, Ho K. ; Park, Jinhong ; Jeon, Dong Kyu ; Jo, Sungwoo ; Jo, Minjae ; Namkung, Wan. / Ani9, a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2. In: PLoS One. 2016 ; Vol. 11, No. 5.
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Ani9, a novel potent small-molecule ANO1 inhibitor with negligible effect on ANO2. / Seo, Yohan; Lee, Ho K.; Park, Jinhong; Jeon, Dong Kyu; Jo, Sungwoo; Jo, Minjae; Namkung, Wan.

In: PLoS One, Vol. 11, No. 5, e0155771, 01.05.2016.

Research output: Contribution to journalArticle

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