2. Academic Validation
  3. Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice

  • ACS Med Chem Lett. 2016 Aug 26;7(10):896-901. doi: 10.1021/acsmedchemlett.6b00190.
Hans E Purkey 1,  Kirk Robarge 1,  Jinhua Chen 2,  Zhongguo Chen 2,  Laura B Corson 1,  Charles Z Ding 2,  Antonio G DiPasquale 3,  Peter S Dragovich 1,  Charles Eigenbrot 1,  Marie Evangelista 1,  Benjamin P Fauber 1,  Zhenting Gao 2,  Hongxiu Ge 2,  Anna Hitz 1,  Qunh Ho 2,  Sharada S Labadie 1,  Kwong Wah Lai 2,  Wenfeng Liu 2,  Yajing Liu 2,  Chiho Li 2,  Shuguang Ma 1,  Shiva Malek 1,  Thomas O'Brien 1,  Jodie Pang 1,  David Peterson 1,  Laurent Salphati 1,  Steve Sideris 1,  Mark Ultsch 1,  BinQing Wei 1,  Ivana Yen 1,  Qin Yue 1,  Huihui Zhang 2,  Aihe Zhou 1
Affiliations

Affiliations

  • 1 Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 WuXi AppTec Co. , Ltd. 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, P. R. China.
  • 3 College of Chemistry, University of California, Berkeley , Berkeley, California 94720, United States.
PMID: 27774125 DOI: 10.1021/acsmedchemlett.6b00190
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 IC50 in a MiaPaca2 cell line. Optimization of the series led to 29, a potent cell active molecule (MiaPaca2 IC50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.

Keywords

Lactate dehydrogenase; X-ray crystal structure; glycolysis; structure-based design; tumor metabolism.

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