CFTR Inhibitor-172

The cystic fibrosis (CF) gene encodes a cAMP-regulated chloride channel, the CF transmembrane conductance regulator (CFTR).¹ CFTR inhibitor-172 is a thiazolidinone that selectively blocks the CFTR channel (K_i = 300 nM) in a voltage-independent manner.² It appears to directly modulate the gating of chloride at the channel and does not prevent elevation of cAMP or inhibit other pumps or channels.^2,3 In mice, CFTR inhibitor-172 prevents cholera toxin-induced fluid secretion in the small intestine, when given by intraperitoneal injection.^2,4 It slows cyst growth in animal models of polycystic kidney disease.⁵ As CFTR also modulates glutathione (GSH) efflux, CFTR inhibitor-172 can affect intracellular GSH concentration and reactive oxygen species balance.^6,7,8

WARNING This product is not for human or veterinary use.

1. Derand, R., Bulteau-Pignoux, L., and Becq, F. The cystic fibrosis mutation G551D alters the non-Michaelis-Menten behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) channel and abolishes the inhibitory genistein binding site. The Journal of Biological Chemisty 277(39), 35999-36004 (2002).

2. Ma, T., Thiagarajah, J.R., Yang, H., et al. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J. Clin. Invest. 110(11), 1651-1658 (2002).

3. Taddei, A., Folli, C., Zegarra-Moran, O., et al. Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker. FEBS Lett. 558(1-3), 52-56 (2004).

4. Sonawane, N.D., Hu, J., Muanprasat, C., et al. Luminally active, nonabsorbable CFTR inhibitors as potential therapy to reduce intestinal fluid loss in cholera. The FASEB Journal 20(1), 130-132 (2006).

5. Yang, B., Sonawane, N.D., Zhao, D., et al. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J. Am. Soc. Nephrol. 19(7), 1300-1310 (2008).

6. Duranton, C., Rubera, I., Cougnon, M., et al. CFTR is involved in the fine tuning of intracellular redox status: Physiological implications in cystic fibrosis. Am. J. Pathol. 181(4), 1367-1377 (2012).

7. l'Hoste, S., Chargui, A., Belfodil, R., et al. CFTR mediates apoptotic volume decrease and cell death by controlling glutathione efflux and ROS production in cultured mice proximal tubules. Am. J. Physiol. Renal Physiol. 298(2), F435-F453 (2010).

8. Rubera, I., Duranton, C., Melis, N., et al. Role of CFTR in oxidative stress and suicidal death of renal cells during cisplatin-induced nephrotoxicity. Cell Death Dis. 4(10), e817 (2013).