Identification and characterization of a novel Anoctamin 1 inhibitor and its anticancer effects

Abstract

Anoctamin 1 (ANO1 also known as TMEM16A) is a calcium‐activated chloride channel that is amplified in various carcinomas including prostate cancer, esophageal cancer, breast cancer, and pancreatic cancer, and its overexpression promotes cell proliferation and cell migration in various cancer cells. A cell base‐screening revealed that (E)‐1‐(7,7‐dimethyl‐7Hfuro[2,3‐f]chromen‐2‐yl)‐3‐(1H‐pyrrol‐2‐yl)prop‐2‐en‐1‐one (Ani‐E1) is a novel, potent and selective ANO1 inhibitor with an IC50 value of 1.23 μM. Ani‐E1 showed 144 times stronger activity on ANO1 inhibition than ANO2 inhibition and did not alter the chloride channel activity of CFTR and the intracellular calcium signaling. Notably, Ani‐E1 strongly decreased cell viability of PC‐3 and FaDu cells expressing high levels of ANO1 with a decrease in ANO1 protein levels. In addition, Ani‐E1 significantly enhanced apoptosis via activation of caspase 3 and cleavage of PARP in PC‐3 and FaDu cells. This study shows that a novel ANO1 inhibitor, Ani‐E1, can be a potential candidate for the treatment of cancers overexpressing ANO1, such as prostate cancer and esophageal cancer.Support or Funding InformationWe thank the National Research Foundation of Korea (NRF‐2017R1A2A2A05069364 and 53 NRF‐2018R1A6A1A03023718, NRF‐2019R1I1A1A01061117) for generous financial support. This research was supported (in part) by Yonsei University Research Fund (Post Doc. Researcher Supporting Program) of 2019 (project no.: 2019‐12‐0013).