title: 2',6'-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine S-adenosyltransferase-2.
abstract: Inhibition of the catalytic subunit of the heterodimeric methionine S-adenosyl transferase-2 (MAT2A) with fluorinated N,N-dialkylaminostilbenes (FIDAS agents) offers a potential avenue for the treatment of liver and colorectal cancers where upregulation of this enzyme occurs. A study of structure-activity relationships led to the identification of the most active compounds as those with (1) either a 2,6-difluorostyryl or 2-chloro-6-fluorostyryl subunit, (2) either an N-methylamino or N,N-dimethylamino group attached in a para orientation relative to the 2,6-dihalostyryl subunit, and (3) either an N-methylaniline or a 2-(N,N-dimethylamino)pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which the FIDAS agents inhibit MAT2A. The active FIDAS agents may inhibit cancer cells through alterations of methylation reactions essential for cancer cell survival and growth.
authors.affiliation: Department of Molecular and Cellular Biochemistry, ‡Department of Pharmaceutical Sciences, College of Pharmacy, §Center for Pharmaceutical Research and Innovation, and ∥Markey Cancer Center, University of Kentucky , Lexington, Kentucky 40506-0509, United States.
authors.forename: Vitaliy M
authors.initials: VM
authors.lastname: Sviripa
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Andrii G
authors.initials: AG
authors.lastname: Balia
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
authors.forename: Justin R
authors.initials: JR
authors.lastname: Nickell
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yu
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
authors.forename: David S
authors.initials: DS
authors.lastname: Watt
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D021122:Protein Subunits / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D011725:Pyridines; D011743:Pyrimidines; D013267:Stilbenes; C527161:MAT2A protein, human; D008716:Methionine Adenosyltransferase