2. Academic Validation
  3. Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties

Pyrazole-Based Lactate Dehydrogenase Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties

  • J Med Chem. 2020 Oct 8;63(19):10984-11011. doi: 10.1021/acs.jmedchem.0c00916.
Ganesha Rai 1,  Daniel J Urban 1,  Bryan T Mott 1,  Xin Hu 1,  Shyh-Ming Yang 1,  Gloria A Benavides 2,  Michelle S Johnson 2,  Giuseppe L Squadrito 2,  Kyle R Brimacombe 1,  Tobie D Lee 1,  Dorian M Cheff 1,  Hu Zhu 1,  Mark J Henderson 1,  Katherine Pohida 1,  Gary A Sulikowski 3,  David M Dranow 4,  Md Kabir 1,  Pranav Shah 1,  Elias Padilha 1,  Dingyin Tao 1,  Yuhong Fang 1,  Plamen P Christov 3,  Kwangho Kim 3,  Somnath Jana 3,  Pavan Muttil 5,  Tamara Anderson 5,  Nitesh K Kunda 5,  Helen J Hathaway 5,  Donna F Kusewitt 6,  Nobu Oshima 7,  Murali Cherukuri 7,  Douglas R Davies 4,  Jeffrey P Norenberg 5,  Larry A Sklar 6,  William J Moore 8,  Chi V Dang 9 10,  Gordon M Stott 8,  Leonard Neckers 7,  Andrew J Flint 8,  Victor M Darley-Usmar 2,  Anton Simeonov 1,  Alex G Waterson 3,  Ajit Jadhav 1,  Matthew D Hall 1,  David J Maloney 1
Affiliations

Affiliations

  • 1 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 2 Mitochondrial Medicine Laboratory, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
  • 3 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4 Beryllium Discovery Corp., 7869 Day Road West, Bainbridge Island, Washington 98110, United States.
  • 5 College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, United States.
  • 6 Dept of Pathology, University of New Mexico Cancer Center, Albuquerque, New Mexico 87131, United States.
  • 7 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, Maryland 20892, United States.
  • 8 NExT Program Support, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
  • 9 Abramson Cancer Center, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
  • 10 Ludwig Institute for Cancer Research, New York, New York 10017, United States.
PMID: 32902275 DOI: 10.1021/acs.jmedchem.0c00916
Abstract

Lactate Dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation of reduced nicotinamide adenine dinucleotide as the final step in the glycolytic pathway. Glycolysis plays an important role in the metabolic plasticity of Cancer cells and has long been recognized as a potential therapeutic target. Thus, potent, selective inhibitors of LDH represent an attractive therapeutic approach. However, to date, pharmacological agents have failed to achieve significant target engagement in vivo, possibly because the protein is present in cells at very high concentrations. We report herein a lead optimization campaign focused on a pyrazole-based series of compounds, using structure-based design concepts, coupled with optimization of cellular potency, in vitro drug-target residence times, and in vivo PK properties, to identify first-in-class inhibitors that demonstrate LDH inhibition in vivo. The lead compounds, named NCATS-SM1440 (43) and NCATS-SM1441 (52), possess desirable attributes for further studying the effect of in vivo LDH inhibition.

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