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Discovery and Optimization of 2H-1 lambda(2)-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer

  1. Author:
    Rohde, Jason M.
    Karavadhi, Surendra
    Pragani, Rajan
    Liu, Li
    Fang, Yuhong
    Zhang, Weihe
    McIver, Andrew
    Zheng, Hongchao
    Liu, Qingyang
    Davis, Mindy
    Urban, Daniel J.
    Lee, Tobie D.
    Cheff, Dorian M.
    Hollingshead,Melinda
    Henderson, Mark J.
    Martinez, Natalia J.
    Brimacombe, Kyle R.
    Yasgar, Adam
    Zhao, Wei
    Klumpp-Thomas, Carleen
    Michael, Sam
    Covey, Joseph
    Moore,Bill
    Stott, Gordon M.
    Li, Zhuyin
    Simeonov, Anton
    Jadhav, Ajit
    Frye, Stephen
    Hall, Matthew D.
    Shen, Min
    Wang, Xiaodong
    Patnaik, Samarjit
    Boxer, Matthew B.

  2. Author Address

    NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA.Univ N Carolina, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Ctr Integrat Chem Biol & Drug Discovery, Chapel Hill, NC 27514 USA.NCI, Biol Testing Branch, Dev Therapeut Program, Frederick, MD 21702 USA.NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Rockville, MD 20850 USA.Leidos Biomed Res Inc, NExT Program Support, Appl Dev Res Directorate, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA.
    1. Year: 2021
    2. Date: Apr 22
  2. Journal: Journal of Medicinal Chemistry
  3. AMER CHEMICAL SOC,
    1. 64
    2. 8
    3. Pages: 4913-4946
  5. Type of Article: Article
  6. ISSN: 0022-2623
  1. Abstract:

    Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1 lambda(2)-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

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External Sources

  1. View Full Text
  2. DOI: 10.1021/acs.jmedchem.1c00019
  3. PMID: 33822623
  4. View record in Web of Science®
  5. WOS: 000644437100034

Library Notes

  1. Fiscal Year: FY2020-2021
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