Abstract
The small-molecule specific inhibitor, CFTRinh-172, is the standard reference for the researches. The progresses of CFTRinh-172 in chemical structure, mechanisms of action, and pharmacokinetics were summarizes in this review. CFTRinh-172 plays an important role in the treatment and drug development of malignant diseases such as cholera, polycystic kidney disease and leukemia. Moreover, CFTRinh-172 is the specific molecular inhibitor of the CFTR chloride channel. However, the side-effects and the poor water solubility restrict its application.
Publication Date
10-28-2018
First Page
179
Last Page
184
DOI
10.13652/j.issn.1003-5788.2018.10.036
Recommended Citation
Jian, LUAN
(2018)
"High-throughput screening and study of CFTR specific inhibitor-CFTRinh-172,"
Food and Machinery: Vol. 34:
Iss.
10, Article 36.
DOI: 10.13652/j.issn.1003-5788.2018.10.036
Available at:
https://www.ifoodmm.cn/journal/vol34/iss10/36
References
[1] RIODAN J R, ROMMENS J M, KEREM B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA[J]. Science, 1989, 245(4 922): 1 066-1 073.
[2] CHENG Seng, GREGORY Richard J, MARSHALL John, et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis[J]. Cell, 1990, 63(4): 827-834.
[3] WELSH M J, SMITH A E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis[J]. Cell, 1993, 73(7): 1 251-1 254.
[4] WARD C L, OMURA S, KOPITO R R. Degradation of CFTR by the ubiquitin-proteasome pathway[J]. Cell, 1995, 83(1): 121-127.
[5] STUTTS M J, CANESSA C M, OLSEN J C, et al. CFTR as a cAMP-dependent regulator of sodium channels[J]. Science, 1995, 269(5 225): 847-850.
[6] WANGENMANN P, WITTNER M, DI STEFANO A, et al. Cl--channel blockers in the thick ascending limb of the loop of Henle Structure activity relationship[J]. Pflügers Archiv, 1986, 407(2): S128-S141.
[7] SHEPPARD D N, WELSH M J. Effect of ATP-sensitive K-channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents[J]. J Gen Physiol, 1992, 100: 573-591.
[8] ZHEN Zhou, HU Sheng-hui, HWANG Tzyh-chang. Probing an open CFTR pore with organic anion blockers[J]. The Journal of General Physiology, 2002, 120(5): 647-662.
[9] THIAGARAJAH J R, VERKMAN A S. CFTR pharmacology and its role in intestinal fluid secretion[J]. Current Opinion in Pharmacology, 2003, 3(6): 594-599.
[10] MORRIS A P, SCOTT J K, BALL J M, et al. NSP4 elicits age-dependent diarrhea and Ca2+-mediated I: influx into intestinal crypts of CF mice[J]. Am J Physiol, 1999, 277: G431-G444.
[11] GALIETTA L J, HAGGIE P M, VERKMAN A S. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities[J]. FEBS Lett., 2001, 499(3): 220-224.
[12] MA Tong-hui, VETRIVEL L, YANG Hong, et al. High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening[J]. J. Biol. Chem., 2002, 277(40): 37 235-37 241.
[13] MA Tong-hui, THIAGARAJAH Jay R, YANG Hong, et al. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion[J]. J. Clin. Invest., 2002, 110(11): 1 651-1 658.
[14] ABHINIT M, GHODKE M, PRATIMA N A. Exploring potential of 4-thiazolidinone: a brief review[J]. Int J Pharm Pharm Sci, 2009, 1(1): 47-64.
[15] SONAWANE N D, VERKMAN A S. Thiazolidinone CFTR inhibitors with improved water solubility identified by structure-activity analysis[J]. Bioorganic & Medicinal Chemistry, 2008, 16(17): 8 187-8 195.
[16] TADDEI A, FOLLI C, ZEGARRA-MORAN O, et al. Altered channel gating mechanism for CFTR inhibition by a high-affinity thiazolidinone blocker[J]. FEBS Lett, 2004, 558(1/2/3): 52-56
[17] AL-AWQATI Q. Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors[J]. The Journal of Clinical Investigation, 2002, 110(11): 1 599.
[18] KOPEIKIN Z, SOHMA Y, LI Min, et al. On the mechanism of CFTR inhibition by a thiazolidinone derivative[J]. The Journal of General Physiology, 2010, 136(6): 659-671.
[19] THIAGARAJAH J R, VERKMAN A S. CFTR inhibitors for treating diarrheal disease[J]. Clinical Pharmacology & Therapeutics, 2012, 92(3): 287-290.
[20] SONAWANE N D, MUANPRASAT C, NAGATANI R, et al. In vivo pharmacology and antidiarrheal efficacy of a thiazolidinone CFTR inhibitor in rodents[J]. Journal of Pharmaceutical Sciences, 2005, 94(1): 134-143.
[21] BARRETT K E, KEELY S J. Chloride secretion by the intestinal epithelium (molecular basis and regulatory aspects)[J]. Annu Rev Physiol, 2000, 62: 535-572.
[22] THIAGARAJAH J R, VERKMAN A S. CFTR pharmacology and its role in intestinal fluid secretion[J]. Current Opinion in Pharmacology, 2003, 3(6): 594-599.
[23] THIAGARAJAH J R, VERKMAN A S. New drug targets for cholera therapy[J]. Trends in Pharmacological Sciences, 2005, 26(4): 172-175.
[24] THIAGARAJAH J R, BROADBENT T, HSIEH E, et al. Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor[J]. Gastroenterology, 2004, 126(2): 511-519.
[25] LI Hong-yu, FINDLAY I A, SHEPPARD D N. The relationship between cell proliferation, Cl- secretion, and renal cyst growth: a study using CFTR inhibitors[J]. Kidney Int, 2004, 66: 1 926-1 938.
[26] MAGENHEIMER B S, ST JOHN P L, ISOM K S, et al. Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na+, K+, 2Cl- co-transporter-dependent cystic dilation[J]. J Am Soc Nephrol, 2006, 17: 3 424-3 437.
[27] SHIBAZAKI S, YU Zhi-heng, NISHIO S, et al. Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1[J]. Hum Mol Genet, 2008, 17: 1 505-1 516.
[28] YANG Bao-xue, SONAWANE N D, ZHAO Dan, et al. Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease[J]. Journal of the American Society of Nephrology, 2008, 19(7): 1 300-1 310.
[29] YANG Xi, GONG Yu-ping. The High Expression of CFTR in Ph+ acute leukemia regulates the BCR-ABL and Wnt/-Catenin signaling pathway via interaction with PP2AProtein[J]. Blood, 2015, 126(23): 1 252.
[30] MCWILLIAMS R R, PETERSEN G M, RABE K G, et al. Cystic brosis transmembrane conductance regulator CFTR) gene mutations and risk for pancreatic adenocarcinoma[J]. Cancer, 2010, 116: 203-209.
[31] YAN Tian-you, LENG Ya-mei, YANG Xi, et al. High-expressing cystic fibrosis transmembrane conductance regulator interacts with histone deacetylase 2 to promote the development of Ph+ leukemia through the HDAC2-mediated PTEN pathway[J]. Leukemia Research, 2017, 57: 9-19.
[32] 南虎松, 尹明姬, 金春姬. CFTR对TF1细胞活力和凋亡的影响及相关机制[J]. 中国病理生理杂志, 2017, 33(12): 2 202-2 207.
[33] FIELD M. Intestinal ion transport and the pathophysiology of diarrhea[J]. J Clin Invest, 2003, 111: 931-943
[34] TERRYN S, HO A, BEAUWENS R, et al. Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease[J]. Biochim Biophys Acta, 2011, 1 812: 1 314-1 321.
[35] MUANPRASAT C, SONAWANE N D, SALINAS D, et al. Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy[J]. The Journal of General Physiology, 2004, 124(2): 125-137.
[36] HOSTOS Eugenio L de, CHOY Robert K M, NGUYEN Tue. Developing novel antisecretory drugs to treat infectious diarrhea[J]. Fr Mdnal Hmry, 2011, 3(10): 1 317-1 325.
[37] SCHWERTSCHLAG U, KUMAR A, KOCHHAR S, et al. Mo1675 pharmacokinetics and tolerability of iOWH032, an inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, in normal volunteers and cholera patients[J]. Garonrology, 2014(5 suppl 1): S-633-S-633.
[38] TRADTRANTIP Lukmanee, SONAWANE N D, NAMK-UNG Wan, et al. Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model[J]. Journal of Medicinal Chemistry, 2009, 52(20): 6 447-6 455.
[39] LUAN Jian, ZHANG Yao-fang, YU Bo, et al. Oridonin: A small molecule inhibitor of cystic fibrosis transmembrane conductance regulator (CFTR) isolated from traditional Chinese medicine[J]. Fitoterapia, 2015, 100: 88-94.
[40] SCHUIER M, SIES H, ILLEK B, et al. Cocoa-related flavonoids inhibit CFTR-mediated chloride transport across T84 human colon epithelia[J]. The Journal of Nutrition, 2005, 135(10): 2 320-2 325.
[41] CHEN Lei, YU Bo, ZHANG Yao-fang, et al. Bioactivity-guided fractionation of an antidiarrheal chinese herb rhodiola kirilowii (regel) maxim reveals (-)-epicatechin-3-gallate and (-)-epigallocatechin-3-gallate as inhibitors of cystic fibrosis transmembrane conductance regulator[J]. PloS One, 2015, 10(3): e0119122.
[42] KELLY M, TRUDEL S, BROUILLARD F, et al. Cystic fibrosis transmembrane regulator inhibitors CFTRinh-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition[J]. Journal of Pharmacology and Experimental Therapeutics, 2010, 333(1): 60-69.