title: Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.
abstract: A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC50in a MiaPaca2 cell line. Optimization of the series led to29, a potent cell active molecule (MiaPaca2 IC50= 0.67 μM) that also possessed good exposure when dosed orally to mice.
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Hans E
authors: HE
authors: Purkey
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Kirk
authors: K
authors: Robarge
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Jinhua
authors: J
authors: Chen
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Zhongguo
authors: Z
authors: Chen
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Laura B
authors: LB
authors: Corson
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Charles Z
authors: CZ
authors: Ding
authors: College of Chemistry, University of California, Berkeley , Berkeley, California 94720, United States.
authors: Antonio G
authors: AG
authors: DiPasquale
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Peter S
authors: PS
authors: Dragovich
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Charles
authors: C
authors: Eigenbrot
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Marie
authors: M
authors: Evangelista
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Benjamin P
authors: BP
authors: Fauber
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Zhenting
authors: Z
authors: Gao
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Hongxiu
authors: H
authors: Ge
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Anna
authors: A
authors: Hitz
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Qunh
authors: Q
authors: Ho
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Sharada S
authors: SS
authors: Labadie
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Kwong Wah
authors: KW
authors: Lai
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Wenfeng
authors: W
authors: Liu
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Yajing
authors: Y
authors: Liu
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Chiho
authors: C
authors: Li
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Shuguang
authors: S
authors: Ma
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Shiva
authors: S
authors: Malek
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Thomas
authors: T
authors: O'Brien
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Jodie
authors: J
authors: Pang
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: David
authors: D
authors: Peterson
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Laurent
authors: L
authors: Salphati
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Steve
authors: S
authors: Sideris
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Mark
authors: M
authors: Ultsch
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: BinQing
authors: B
authors: Wei
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Ivana
authors: I
authors: Yen
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Qin
authors: Q
authors: Yue
authors: WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
authors: Huihui
authors: H
authors: Zhang
authors: Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Aihe
authors: A
authors: Zhou
keywords: Lactate dehydrogenase; X-ray crystal structure; glycolysis; structure-based design; tumor metabolism