The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, belonging to the ABC family of transporters, lies at the heart of hypersecretion associated with AWD (acute watery diarrhea) caused by enterotoxigenic bacteria. IOWH032, chloride channel blocker, is a synthetic CFTR inhibitor with antisecretory activity developed by OneWorld Health and currently in Phase I clinical trials to treat diarrhea[3]. During a ~50s extracellular exposure to 5 nM IOWH-032, hCFTR was blocked. Specificly, IOWH-032 blocked hCFTR rapidly in a concentration-dependent manner with apparent Kd of 6.1 nM. Through time, it also potentiated hCFTR in a concentration-dependent manner with an apparent Kd of 0.64 nM. Moreover, 20 nM IOWH-032 potentiated F508del-hCFTR expressed in Xenopus oocytes[4]. In two animal models of secretory diarrhea, injection of iOWH032 directly into intestinal loops inhibited secretion by nearly 70% as measured on a semi-quantitative fecal output scale[3].
IOWH-032 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Vero cells
5-20 µM
72 hours
Inhibited HSV-1 and HSV-2-induced cytopathic effects
Viruses. 2024 Aug 16;16(8):1308
MucilAir™ wt/wt-CFTR
10 µM
1 hour
Inhibition of CFTR function, reducing SARS-CoV-2 viral replication
Cells. 2022 Apr 15;11(8):1347
CFBE41o- WT cells
10 µM
1 hour
Inhibition of CFTR function, significantly reducing SARS-CoV-2 viral replication
Cells. 2022 Apr 15;11(8):1347
wt/wt-CFTR MucilAir™ cells
10 μM
0, 24, 48 hours
Assessment of the effect of IOWH-032 on tissue integrity, showing no significant reduction in tissue integrity after 48 h of treatment at 10 μM.
Cells. 2023 Feb 28;12(5):776
CFBE41o- WT cells
0.1, 1, 5, 7, 10, 20, 30, 50, 100 μM
1, 24, 48 hours
Evaluation of cytotoxicity of IOWH-032, showing CC50 > 50 μM at 48 h post-treatment, with no significant cytotoxicity at the CFTR inhibitory concentration IC50 (8 μM).
Cells. 2023 Feb 28;12(5):776
Human HaCaT keratinocytes cells
5-20 µM
24 hours
Suppressed HSV-1 and HSV-2 replication, reduced viral glycoprotein D synthesis and viral gene expression
Viruses. 2024 Aug 16;16(8):1308
human lung cancer cells
4 μM
Evaluated cytotoxicity of IOWH-032, observed ~50% reduction in cell viability
ACS Chem Biol. 2024 Jul 19;19(7):1593-1603
monkey kidney cells
4 μM
Evaluated cytotoxicity of IOWH-032, observed ~50% reduction in cell viability
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