title: The Tumor-Selective Cytotoxic Agent β-Lapachone is a Potent Inhibitor of IDO1.
abstract: β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania. ; Department of Biochemistry, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Hollie E
authors.initials: HE
authors.lastname: Flick
authors.forename: Judith M
authors.initials: JM
authors.lastname: Lalonde
authors.forename: William P
authors.initials: WP
authors.lastname: Malachowski
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
keywords: 3-dioxygenase; IDO; beta-lapachone; cancer; immunotherapy; indoleamine 2; inhibitor; naphthoquinone; tryptophan
references.citation: Cancer Res. 2010 Mar 1;70(5):1845-53
references.pmid: 20160032
references.citation: J Med Chem. 2009 Dec 10;52(23):7364-7
references.pmid: 19507862
references.citation: Proteins. 2003 Feb 15;50(3):437-50
references.pmid: 12557186
references.citation: Science. 2002 Jul 12;297(5579):259-63
references.pmid: 12114629
references.citation: Cancer Res. 2005 Sep 15;65(18):8065-8
references.pmid: 16166276
references.citation: Nat Rev Drug Discov. 2002 Aug;1(8):609-20
references.pmid: 12402501
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):4963-7
references.pmid: 2740334
references.citation: Adv Protein Chem. 2003;66:27-85
references.pmid: 14631816
references.citation: Cancer Res. 1992 Sep 1;52(17):4752-7
references.pmid: 1324793
references.citation: Biochem Pharmacol. 1996 Feb 9;51(3):275-83
references.pmid: 8573194
references.citation: Cancer Res. 2007 Jan 15;67(2):792-801
references.pmid: 17234791
references.citation: Mutat Res. 1998 Jun 5;401(1-2):55-63
references.pmid: 9639674
references.citation: Protein Sci. 1993 Mar;2(3):472-5
references.pmid: 8453383
references.citation: J Mol Biol. 1999 Jan 29;285(4):1735-47
references.pmid: 9917408
references.citation: Biochem Pharmacol. 1999 Apr 1;57(7):763-74
references.pmid: 10075082
references.citation: Nat Med. 2011 Aug 28;17(9):1094-100
references.pmid: 21873989
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11832-7
references.pmid: 17609380
references.citation: FASEB J. 1991 Aug;5(11):2516-22
references.pmid: 1907934
references.citation: J Exp Med. 1999 Aug 2;190(3):355-66
references.pmid: 10430624
references.citation: J Comput Chem. 1999 May;20(7):730-748
references.pmid: 34376036
references.citation: Nat Med. 2005 Mar;11(3):312-9
references.pmid: 15711557
references.citation: Curr Opin Cell Biol. 2004 Dec;16(6):663-9
references.pmid: 15530778
references.citation: Cancer Discov. 2012 Aug;2(8):722-35
references.pmid: 22822050
references.citation: Protein Expr Purif. 2000 Jun;19(1):22-9
references.pmid: 10833386
references.citation: Curr Cancer Drug Targets. 2009 Dec;9(8):938-52
references.pmid: 20025603
references.citation: J Biol Chem. 2001 Jun 1;276(22):19150-9
references.pmid: 11279125
references.citation: J Comput Chem. 1999 May;20(7):720-729
references.pmid: 34376030
references.citation: J Med Chem. 2008 Mar 27;51(6):1706-18
references.pmid: 18318466
references.citation: Br J Cancer. 1997;76(7):923-9
references.pmid: 9328153
references.citation: Proteins. 2005 Mar 1;58(4):836-44
references.pmid: 15651036
references.citation: Mol Med. 1999 Apr;5(4):232-9
references.pmid: 10448645
references.citation: Mol Med. 2000 Dec;6(12):1008-15
references.pmid: 11474117
references.citation: Biochemistry. 1989 Jun 27;28(13):5392-9
references.pmid: 2789076
references.citation: Oncogene. 2008 May 1;27(20):2851-7
references.pmid: 18026137
references.citation: Int J Tryptophan Res. 2011;4:29-37
references.pmid: 22084601
references.citation: Cancer Metastasis Rev. 1993 Jun;12(2):103-17
references.pmid: 8375015
references.citation: Curr Protoc Pharmacol. 2002 Feb;Chapter 5:Unit5.24
references.pmid: 21959766
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2611-6
references.pmid: 16477023
references.citation: J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
references.pmid: 2359136
references.citation: Mol Biochem Parasitol. 2001 Jul;115(2):249-56
references.pmid: 11420111
references.citation: J Biol Chem. 2000 Feb 25;275(8):5416-24
references.pmid: 10681517
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17073-8
references.pmid: 18952840
references.citation: J Biol Chem. 1993 Oct 25;268(30):22463-8
references.pmid: 8226754
references.citation: Science. 1998 Aug 21;281(5380):1191-3
references.pmid: 9712583
references.citation: Cell Cycle. 2006 Sep;5(17):2029-35
references.pmid: 16969131
references.citation: J Exp Med. 1994 Feb 1;179(2):523-32
references.pmid: 7507508
references.citation: J Med Chem. 2006 Jan 26;49(2):684-92
references.pmid: 16420054
references.citation: Cancer J. 2010 Jul-Aug;16(4):354-9
references.pmid: 20693847
references.citation: Oncol Res. 1994;6(10-11):525-32
references.pmid: 7620221