title: A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site.
abstract: Human fatty acid synthase (hFAS) is a complex, multifunctional enzyme that is solely responsible for the de novo synthesis of long chain fatty acids. hFAS is highly expressed in a number of cancers, with low expression observed in most normal tissues. Although normal tissues tend to obtain fatty acids from the diet, tumor tissues rely on de novo fatty acid synthesis, making hFAS an attractive metabolic target for the treatment of cancer. We describe here the identification of GSK2194069, a potent and specific inhibitor of the β-ketoacyl reductase (KR) activity of hFAS; the characterization of its enzymatic and cellular mechanism of action; and its inhibition of human tumor cell growth. We also present the design of a new protein construct suitable for crystallography, which resulted in what is to our knowledge the first co-crystal structure of the human KR domain and includes a bound inhibitor.
authors.affiliation: 1] Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA. [2].
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.affiliation: 1] Platform Technology and Science, GlaxoSmithKline, Collegeville, Pennsylvania, USA. [2].
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: 1] Platform Technology and Science, GlaxoSmithKline, Research Triangle Park, North Carolina, USA. [2].
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Williams
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Ramona N
authors.initials: RN
authors.lastname: Plant
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Totoritis
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Briand
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Burkhart
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
mesh_terms: D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011759:Pyrrolidines / Q000378:metabolism* / Q000494:pharmacology*; D014230:Triazoles / Q000378:metabolism* / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; C000592442:GSK2194069; D011759:Pyrrolidines; D014230:Triazoles; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D064429:Fatty Acid Synthases
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