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
  • 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.
Products