title: Identification of 2-amino-5-aryl-pyrazines as inhibitors of human lactate dehydrogenase.
abstract: A 2-amino-5-aryl-pyrazine was identified as an inhibitor of human lactate dehydrogenase A (LDHA) via a biochemical screening campaign. Biochemical and biophysical experiments demonstrated that the compound specifically interacted with human LDHA. Structural variation of the screening hit resulted in improvements in LDHA biochemical inhibition and pharmacokinetic properties. A crystal structure of an improved compound bound to human LDHA was also obtained and it explained many of the observed structure-activity relationships.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: benjampf@gene.com.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.forename: Laura B
authors.initials: LB
authors.lastname: Corson
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Liu
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Keith
authors.initials: K
authors.lastname: Pitts
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.forename: Erica
authors.initials: E
authors.lastname: VanderPorten
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011719:Pyrazines; D007770:L-Lactate Dehydrogenase
keywords: Lactate dehydrogenase; Pyrazine; Tumor metabolism; X-ray crystal structure