1. Academic Validation
  2. 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.
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.

Figures
Products