title: Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase.
abstract: A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Panayotis C
authors.initials: PC
authors.lastname: Theodoropoulos
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Gonzales
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Winterton
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0002-8499-5513
authors.initials: C
authors.lastname: Rodriguez-Navas
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: McKnight
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Morlock
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Hanson
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Cross
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Owen
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Moreno
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lemoff
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.|Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nijhawan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D055808:Drug Discovery / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010072:Oxamic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D011485:Protein Binding; D012627:Sebaceous Glands / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C492722:CYP4F11 protein, human; D013230:Stearoyl-CoA Desaturase; D010072:Oxamic Acid; C008728:oxamide
references.citation: Oncogene. 2006 Mar 13;25(11):1679-91
references.pmid: 16550168
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3077-82
references.pmid: 12629214
references.citation: J Proteome Res. 2004 Sep-Oct;3(5):958-64
references.pmid: 15473683
references.citation: Mol Cancer Res. 2011 Nov;9(11):1551-61
references.pmid: 21954435
references.citation: Nat Struct Mol Biol. 2015 Jul;22(7):581-5
references.pmid: 26098317
references.citation: Int J Oncol. 2008 Oct;33(4):839-50
references.pmid: 18813799
references.citation: Anticancer Agents Med Chem. 2014 Jan;14(1):115-26
references.pmid: 23869779
references.citation: Bioinformatics. 2010 Apr 15;26(8):1131-2
references.pmid: 20189941
references.citation: J Invest Dermatol. 2013 Aug;133(8):2091-4
references.pmid: 23446987
references.citation: J Med Chem. 2014 Jun 26;57(12):5039-56
references.pmid: 24295027
references.citation: Trends Cell Biol. 2014 Aug;24(8):472-8
references.pmid: 24985940
references.citation: Nature. 2015 Aug 13;524(7564):252-6
references.pmid: 26098370
references.citation: Cell. 2013 Oct 24;155(3):552-66
references.pmid: 24243015
references.citation: PLoS One. 2012;7(3):e33823
references.pmid: 22457791
references.citation: Biochem J. 1999 May 15;340 ( Pt 1):255-64
references.pmid: 10229681
references.citation: J Med Chem. 2007 Jun 28;50(13):3086-100
references.pmid: 17530838
references.citation: Bioinformatics. 2004 Jun 12;20(9):1466-7
references.pmid: 14976030
references.citation: Cancer Res. 2004 Dec 15;64(24):9027-34
references.pmid: 15604268
references.citation: J Med Chem. 2013 Jan 24;56(2):568-83
references.pmid: 23245208
references.citation: Crit Rev Toxicol. 2002 Sep;32(5):391-411
references.pmid: 12389869
references.citation: J Biol Chem. 2009 Jul 10;284(28):18559-63
references.pmid: 19363032
references.citation: Cell Rep. 2014 Oct 23;9(2):633-45
references.pmid: 25373903
references.citation: FASEB J. 1996 Feb;10(2):202-4
references.pmid: 8641552
references.citation: Angew Chem Int Ed Engl. 2001 Jun 1;40(11):2004-2021
references.pmid: 11433435
references.citation: Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E28-37
references.pmid: 19066317
references.citation: J Lipid Res. 2012 Aug;53(8):1646-53
references.pmid: 22669918
references.citation: Biochimie. 2010 Mar;92(3):292-306
references.pmid: 20034539
references.citation: Cell. 2006 Mar 24;124(6):1283-98
references.pmid: 16564017
references.citation: Biochim Biophys Acta. 2011 Nov;1811(11):648-56
references.pmid: 21787881
references.citation: Nat Methods. 2007 Mar;4(3):207-14
references.pmid: 17327847
references.citation: Br J Pharmacol. 2001 Jun;133(3):325-9
references.pmid: 11375247
references.citation: Hum Gene Ther. 1998 Jun 10;9(9):1261-73
references.pmid: 9650611
references.citation: Nature. 2012 Mar 29;483(7391):603-7
references.pmid: 22460905
references.citation: Cancer Discov. 2012 May;2(5):401-4
references.pmid: 22588877
references.citation: J Pharmacol Exp Ther. 1983 Jan;224(1):252-7
references.pmid: 6848746
references.citation: J Lipid Res. 2008 Mar;49(3):612-24
references.pmid: 18065749
references.citation: Cell Metab. 2007 Dec;6(6):484-96
references.pmid: 18054317
references.citation: Acc Chem Res. 2004 Jul;37(7):421-9
references.pmid: 15260504
references.citation: PLoS One. 2010;5(6):e11394
references.pmid: 20613975
references.citation: Biochem Pharmacol. 2008 Jun 15;75(12):2263-75
references.pmid: 18433732
references.citation: Cancer Res. 1993 Apr 15;53(8):1794-801
references.pmid: 8467498
references.citation: J Biol Chem. 2004 Sep 3;279(36):37798-807
references.pmid: 15220349
references.citation: Assay Drug Dev Technol. 2008 Feb;6(1):121-9
references.pmid: 18336089
references.citation: Anal Biochem. 1969 May;29(2):300-4
references.pmid: 5792566