title: Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase.
abstract: A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1 μM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48 μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. dragovich.peter@gene.com
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
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: HongXiu
authors.initials: H
authors.lastname: Ge
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: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: Borlan
authors.initials: B
authors.lastname: Pan
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Keith
authors.initials: K
authors.lastname: Pitts
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
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: BinQing
authors.initials: B
authors.lastname: Wei
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.forename: Huihui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xuying
authors.initials: X
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009243:NAD / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D009243:NAD; D007770:L-Lactate Dehydrogenase