title: Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors.
abstract: Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson's disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit submicromolar inhibition constants but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.
authors: Department of Biochemistry and Molecular Biology Indiana University School of Medicine 635 Barnhill Drive, Indianapolis, Indiana 46202, United States.
authors: Cynthia A
authors: CA
authors: Morgan
authors: Thomas D
authors: TD
authors: Hurley
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D050697:Retinal Dehydrogenase; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
references: Biochemistry. 1999 May 11;38(19):6003-11
references: 10320326
references: Curr Pharm Des. 1999 Aug;5(8):607-25
references: 10469894
references: Protein Sci. 1999 Dec;8(12):2784-90
references: 10631996
references: J Biol Chem. 2001 May 4;276(18):15107-16
references: 11134058
references: Free Radic Res. 2000 Nov;33 Suppl:S99-108
references: 11191280
references: Carcinogenesis. 2001 Mar;22(3):433-9
references: 11238183
references: Curr Med Chem. 2001 Jun;8(7):721-38
references: 11375746
references: Mech Dev. 2002 Jan;110(1-2):165-71
references: 11744377
references: Biochemistry. 2002 Jun 4;41(22):7156-68
references: 12033950
references: Enzyme. 1992;46(4-5):239-44
references: 1292933
references: J Hum Genet. 2004;49(3):134-40
references: 14986171
references: Drug Metab Rev. 2004 May;36(2):279-99
references: 15237855
references: Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
references: 15299374
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Acta Crystallogr D Biol Crystallogr. 2005 Apr;61(Pt 4):465-71
references: 15809496
references: Hum Mutat. 2005 Jul;26(1):1-10
references: 15931689
references: Cancer Res. 2005 Sep 15;65(18):8118-24
references: 16166285
references: Crit Rev Toxicol. 2005 Aug;35(7):609-62
references: 16417045
references: Nat Med. 2006 Mar;12(3):307-9
references: 16491085
references: Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):439-50
references: 16552146
references: J Biol Chem. 1975 Oct 10;250(19):7894-8
references: 170275
references: Chem Res Toxicol. 2006 Oct;19(10):1374-8
references: 17040107
references: Pharmacol Rev. 2007 Jun;59(2):125-50
references: 17379813
references: Biochem Biophys Res Commun. 2007 May 11;356(3):792-8
references: 17382292
references: Pharmacogenet Genomics. 2007 Oct;17(10):845-55
references: 17885622
references: Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720
references: 18611112
references: J Med Chem. 2008 Aug 14;51(15):4482-7
references: 18613661
references: Science. 2008 Sep 12;321(5895):1493-5
references: 18787169
references: Chem Biol Interact. 2009 Mar 16;178(1-3):48-55
references: 18952074
references: Blood. 2009 Feb 19;113(8):1670-80
references: 18971422
references: Chem Biol Interact. 2009 Mar 16;178(1-3):36-9
references: 18983993
references: Int J Cancer. 2009 May 1;124(9):2060-70
references: 19132753
references: Free Radic Biol Med. 1991;11(1):81-128
references: 1937131
references: Lab Invest. 2010 Feb;90(2):234-44
references: 20010854
references: Nat Struct Mol Biol. 2010 Feb;17(2):159-64
references: 20062057
references: Nat Med. 2010 Sep;16(9):1024-8
references: 20729865
references: Mol Cancer Ther. 2010 Dec;9(12):3186-99
references: 20889728
references: Stem Cell Rev. 2011 Jun;7(2):292-306
references: 21103958
references: Chem Biol Interact. 2011 May 30;191(1-3):153-8
references: 21349255
references: Biochim Biophys Acta. 2012 Jan;1821(1):198-205
references: 21515404
references: J Biol Chem. 2011 Dec 16;286(50):43486-94
references: 22021038
references: Chem Biol Interact. 2012 Jan 5;195(1):52-60
references: 22079344
references: Pharmacol Rev. 2012 Jul;64(3):520-39
references: 22544865
references: Chem Biol Interact. 2013 Feb 25;202(1-3):22-31
references: 23348497
references: J Med Chem. 2014 Jan 23;57(2):449-61
references: 24387105
references: Chembiochem. 2014 Mar 21;15(5):701-12
references: 24677340
references: Oncogene. 2015 Apr 30;34(18):2297-308
references: 24954508
references: Chem Biol Interact. 2015 Jun 5;234:29-37
references: 25450233
references: Chem Biol Interact. 2015 Jun 5;234:18-28
references: 25512087
references: Methods Enzymol. 1997;276:307-26
references: 27754618
references: J Biol Chem. 1989 Mar 15;264(8):4715-21
references: 2925663
references: J Clin Invest. 1988 Mar;81(3):738-44
references: 3343337
references: J Biol Chem. 1972 Jan 10;247(1):267-72
references: 4336042
references: Proc Natl Acad Sci U S A. 1984 Jan;81(1):258-61
references: 6582480
references: Adv Exp Med Biol. 1995;372:115-22
references: 7484368
references: Blood. 1995 May 15;85(10):2742-6
references: 7742535
references: Alcohol Clin Exp Res. 1993 Aug;17(4):828-31
references: 8214422
references: Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1247-51
references: 8433985
references: Biochemistry. 1996 Apr 9;35(14):4445-56
references: 8605194
references: FASEB J. 1996 Jul;10(9):940-54
references: 8801176
references: Hum Mol Genet. 1998 Sep;7(9):1411-5
references: 9700195
references: Structure. 1998 Dec 15;6(12):1541-51
references: 9862807
references: Biochemistry. 1999 Jan 5;38(1):42-54
references: 9890881