Chromene-3-carboxamide derivatives discovered from virtual screening as potent inhibitors of the tumour maker, AKR1B10.

A human aldose reductase-like protein, AKR1B10 in the aldo-keto reductase (AKR) superfamily, was recently identified as a therapeutic target in the treatment of several types of cancer. In order to identify potential leads for new inhibitors of AKR1B10, we adopted the virtual screening approach using the automated program icm, which resulted in the discovery of several chromene-3-carboxamide derivatives as potent competitive inhibitors. The most potent (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide inhibited the reductase activity of AKR1B10 with a K(i) value of 2.7nM, and the metabolism of farnesal and 4-hydroxynonenal in the AKR1B10-overexpressed cells from 0.1microM with an IC(50) value equal to 0.8microM.

[1]  P. Oates.  Aldose reductase, still a compelling target for diabetic neuropathy. , 2008, Current drug targets.

[2]  B. Sarg,et al.  Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib , 2009, Molecular Cancer Therapeutics.

[3]  Tanaka Akira,et al.  Purification and characterization of human testis aldose and aldehyde reductase , 1991 .

[4]  A. Bhatnagar,et al.  Identification of cardiac oxidoreductase(s) involved in the metabolism of the lipid peroxidation-derived aldehyde-4-hydroxynonenal. , 1998, The Biochemical journal.

[5]  E. Maser,et al.  Development of daunorubicin resistance in tumour cells by induction of carbonyl reduction. , 2000, Biochemical pharmacology.

[6]  C. Wild,et al.  Proteomic screening of a cell line model of esophageal carcinogenesis identifies cathepsin D and aldo-keto reductase 1C2 and 1B10 dysregulation in Barrett's esophagus and esophageal adenocarcinoma. , 2008, Journal of proteome research.

[7]  Keiichiro Suzuki,et al.  Aldehyde reductase gene expression by lipid peroxidation end products, MDA and HNE , 2000, Free radical research.

[8]  D. Cao,et al.  Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels. , 2009, Biochemical and biophysical research communications.

[9]  S. Venz,et al.  PURIFICATION AND CHARACTERIZATION OF AKR1B10 FROM HUMAN LIVER: ROLE IN CARBONYL REDUCTION OF XENOBIOTICS , 2006, Drug Metabolism and Disposition.

[10]  S. Chung,et al.  Overexpression of aldose reductase in liver cancers may contribute to drug resistance , 2001, Anti-cancer drugs.

[11]  B. Springthorpe,et al.  Which Hydroxy? Evidence for Species Differences in the Regioselectivity of Glucuronidation in Rat, Dog, and Human in Vitro Systems and Dog in Vivo , 2006, Drug Metabolism and Disposition.

[12]  Kazuo Kuwata,et al.  Hot spots in prion protein for pathogenic conversion , 2007, Proceedings of the National Academy of Sciences.

[13]  T. Penning,et al.  The aldo-keto reductase superfamily homepage. , 2003, Chemico-biological interactions.

[14]  S. Usui,et al.  Growth suppressing activity for endothelial cells induced from macrophages by carboxymethylated curdlan. , 1997, Bioscience, biotechnology, and biochemistry.

[15]  T. Nakayama,et al.  Aldehyde reductase is a major protein associated with 3-deoxyglucosone reductase activity in rat, pig and human livers. , 1991, The Biochemical journal.

[16]  H. Aburatani,et al.  Aldo-keto reductase family 1, member B10 in uterine carcinomas: a potential risk factor of recurrence after surgical therapy in cervical cancer , 2006, International Journal of Gynecologic Cancer.

[17]  D. Petersen,et al.  Reactions of 4-hydroxynonenal with proteins and cellular targets. , 2004, Free radical biology & medicine.

[18]  K. Bohren,et al.  Mechanism of human aldehyde reductase: characterization of the active site pocket. , 1995, Biochemistry.

[19]  O. El-Kabbani,et al.  Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: probing the active site of the enzyme with molecular modeling and site-directed mutagenesis. , 2009, Biochemical and biophysical research communications.

[20]  Jun Ma,et al.  Aldo–keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention , 2007, International journal of cancer.

[21]  Y. Awasthi,et al.  Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death. , 2008, Free radical biology & medicine.

[22]  T. Flynn,et al.  Sequence and expression levels in human tissues of a new member of the aldo-keto reductase family. , 1998, Biochimica et biophysica acta.

[23]  R. Álvarez,et al.  Aldo-keto reductases from the AKR1B subfamily: retinoid specificity and control of cellular retinoic acid levels. , 2009, Chemico-biological interactions.

[24]  O. El-Kabbani,et al.  Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites , 2007, Cellular and Molecular Life Sciences.

[25]  Angel R de Lera,et al.  Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10 , 2007, Proceedings of the National Academy of Sciences.

[26]  E. Maser,et al.  Role of human aldo-keto-reductase AKR1B10 in the protection against toxic aldehydes. , 2009, Chemico-biological interactions.

[27]  P. Shapiro,et al.  Inhibition of aldose reductase enhances HeLa cell sensitivity to chemotherapeutic drugs and involves activation of extracellular signal-regulated kinases , 2002, Anti-cancer drugs.

[28]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[29]  O. El-Kabbani,et al.  Kinetic studies of AKR1B10, human aldose reductase-like protein: endogenous substrates and inhibition by steroids. , 2009, Archives of biochemistry and biophysics.

[30]  K. Watabe,et al.  Aldo-keto Reductase Family 1 Member B10 Promotes Cell Survival by Regulating Lipid Synthesis and Eliminating Carbonyls* , 2009, The Journal of Biological Chemistry.

[31]  Sheung Tat Fan,et al.  Identification and Characterization of a Novel Human Aldose Reductase-like Gene* , 1998, The Journal of Biological Chemistry.

[32]  T. Flynn,et al.  Human aldose reductase and human small intestine aldose reductase are efficient retinal reductases: consequences for retinoid metabolism. , 2003, The Biochemical journal.

[33]  Hiroyuki Aburatani,et al.  Overexpression of the Aldo-Keto Reductase Family Protein AKR1B10 Is Highly Correlated with Smokers' Non–Small Cell Lung Carcinomas , 2005, Clinical Cancer Research.

[34]  M. Foppiano,et al.  Worldwide pharmacovigilance systems and tolrestat withdrawal , 1997, The Lancet.

[35]  H. Sawada,et al.  Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members. , 2003, Archives of biochemistry and biophysics.

[36]  G. Balendiran,et al.  Inhibiting wild-type and C299S mutant AKR1B10; a homologue of aldose reductase upregulated in cancers. , 2008, European journal of pharmacology.