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Discovery of a novel chalcone derivative inhibiting CFTR chloride channel via AMPK activation and its anti-diarrheal application

Yibcharoenporn, C;Chusuth, P;Jakakul, C;Rungrotmongkol, T;Chavasiri, W;Muanprasat, C;

Secretory diarrhea is one of the most common causes of death world-wild especially in children under 5 years old. Isoliquiritigenin (ISLQ), a plant-derived chalcone, has previously been shown to exert anti-secretory action _in vitro_ and _in vivo_ by inhibiting CFTR Cl- channels. However, its CFTR inhibition potency is considerably low (IC50 > 10 M) with unknown mechanism of action. This study aimed to identify novel chalcone derivatives with improved potency and explore their mechanism of action. Screening of 27 chalcone derivatives identified CHAL-025 as the most potent chalcone analog that reversibly inhibited CFTR-mediated Cl- secretion in T84 cells with an IC50 of 1.5 M. As analyzed by electrophysiological and biochemical analyses, the mechanism of CFTR inhibition by CHAL-025 is through AMP-activated protein kinase (AMPK), a negative regulator of CFTR activity. Furthermore, western blot analyses and molecular dynamics (MD) results suggest that CHAL-025 activates AMPK by binding at the allosteric site of an upstream kinase calcium-calmodulin kinase kinase (CaMKK). Interestingly, CHAL-025 inhibited both cholera toxin (CT) and bile acid-induced Cl- secretion in T84 cells and prevented CT-induced intestinal fluid secretion in mice. Therefore, CHAL-025 represents a promising anti-anti-diarrheal agent that inhibits CFTR Cl- channel activity via CaMKK-AMPK pathways.