title: Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
abstract: Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4–10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
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: Qunh
authors.initials: Q
authors.lastname: Ho
authors.forename: Kwong Wah
authors.initials: KW
authors.lastname: Lai
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Steven
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
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells
chemical_list: D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase