title: Metabolic Enzyme Sulfotransferase 1A1 Is the Trigger for N-Benzyl Indole Carbinol Tumor Growth Suppression.
abstract: In an attempt to identify novel therapeutics and mechanisms to differentially kill tumor cells using phenotypic screening, we identified N-benzyl indole carbinols (N-BICs), synthetic analogs of the natural product indole-3-carbinol (I3C). To understand the mode of action for the molecules we employed Cancer Cell Line Encyclopedia viability profiling and correlative informatics analysis to identify and ultimately confirm the phase II metabolic enzyme sulfotransferase 1A1 (SULT1A1) as the essential factor for compound selectivity. Further studies demonstrate that SULT1A1 activates the N-BICs by rendering the compounds strong electrophiles which can alkylate cellular proteins and thereby induce cell death. This study demonstrates that the selectivity profile for N-BICs is through conversion by SULT1A1 from an inactive prodrug to an active species that induces cell death and tumor suppression.
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: deborah.rothman@novartis.com.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Rothman
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: George
authors.affiliation: Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rasmusson
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Diksha
authors.initials: D
authors.lastname: Bhatia
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Alimov
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Wang
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Kamel
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Hatsis
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Antonin
authors.initials: A
authors.lastname: Tutter
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Michaud
authors.affiliation: Department of Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Earl
authors.initials: E
authors.lastname: McDonald
authors.affiliation: Department of Oncology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Venkatesan
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Farley
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Digan
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Harbinski
authors.affiliation: Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Mithat
authors.initials: M
authors.lastname: Gunduz
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Buckler
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Labow
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tallarico
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Vic E
authors.initials: VE
authors.lastname: Myer
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Department of Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: shaowen.wang@novartis.com.
authors.forename: Shaowen
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000378:metabolism*; D001593:Benzyl Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D001593:Benzyl Compounds; D007211:Indoles; C016517:indole-3-carbinol; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human