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

  1. Author:
    Rai, Ganesha
    Urban, Daniel J.
    Mott, Bryan T.
    Hu, Xin
    Yang, Shyh-Ming
    Benavides, Gloria A.
    Johnson, Michelle S.
    Squadrito, Giuseppe L.
    Brimacombe, Kyle R.
    Lee, Tobie D.
    Cheff, Dorian M.
    Zhu, Hu
    Henderson, Mark J.
    Pohida, Katherine
    Sulikowski, Gary A.
    Dranow, David M.
    Kabir, Md
    Shah, Pranav
    Padilha, Elias
    Tao, Dingyin
    Fang, Yuhong
    Christov, Plamen P.
    Kim, Kwangho
    Jana, Somnath
    Muttil, Pavan
    Anderson, Tamara
    Kunda, Nitesh K.
    Hathaway, Helen J.
    Kusewitt, Donna F.
    Oshima, Nobu
    Cherukuri, Murali
    Davies, Douglas R.
    Norenberg, Jeffrey P.
    Sklar, Larry A.
    Moore, William J.
    Dang, Chi
    Stott,Gordon
    Neckers, Leonard
    Flint,Andrew
    Darley-Usmar, Victor M.
    Simeonov, Anton
    Waterson, Alex G.
    Jadhav, Ajit
    Hall, Matthew D.
    Maloney, David J.

  2. Author Address

    NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA.Univ Alabama Birmingham, Dept Pathol, Mitochondrial Med Lab, Birmingham, AL 35294 USA.Vanderbilt Univ, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA.Beryllium Discovery Corp, Bainbridge Isl, WA 98110 USA.Univ New Mexico, Coll Pharm, Hlth Sci Ctr, Albuquerque, NM 87131 USA.Univ New Mexico, Dept Pathol, Canc Ctr, Albuquerque, NM 87131 USA.NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA.Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Appl Dev Res Directorate, NExT Program Support, Frederick, MD 21702 USA.Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA.Ludwig Inst Canc Res, New York, NY 10017 USA.
    1. Year: 2020
    2. Date: OCT 8
  2. Journal: JOURNAL OF MEDICINAL CHEMISTRY
  3. AMER CHEMICAL SOC,
    1. 63
    2. 19
    3. Pages: 10984-11011
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. 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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External Sources

  1. View Full Text
  2. DOI: 10.1021/acs.jmedchem.0c00916
  3. View record in Web of Science®
  4. WOS: 000580558700020

Library Notes

  1. Fiscal Year: FY2020-2021
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