title: Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
abstract: A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dragovich.peter@gene.com.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fauber
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Boggs
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Corson
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Charles Z
authors.initials: CZ
authors.lastname: Ding
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: HongXiu
authors.initials: H
authors.lastname: Ge
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Giannetti
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Chiho
authors.initials: C
authors.lastname: Li
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Yichin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Ma
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Pitts
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Robarge
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ultsch
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: VanderPorten
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: BinQing
authors.initials: B
authors.lastname: Wei
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yue
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, PR China.
authors.forename: Xuying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Aihe
authors.initials: A
authors.lastname: Zhou
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003512:Cyclohexanones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D007770:L-Lactate Dehydrogenase
keywords: Glycolysis; Lactate dehydrogenase; Tumor metabolism; X-ray crystal structure