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Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors

  1. Author:
    Du,Lin [ORCID]
    Wilson,Brice [ORCID]
    Moore,William
    Dalilian, Masoumeh
    Shenoy, Shilpa R
    Li,Ning
    Martinez Fiesco,Juliana
    Hwang,Jiyeon
    Smith, Emily A
    Wamiru,Antony
    Goncharova,Ekaterina
    Alvarez De La Cruz,Astrid [ORCID]
    Pagadala, Karunakar
    Piswa, Harish K
    Patteti, Venukumar
    Jampana, Veera P
    Manepalli, Prasad
    Nimmala, Ravi
    Marri, Narender R
    Gunuguntla, Mahendar
    Reddy, Jakkidi J
    Schneekloth,John [ORCID]
    Zhang,Ping
    O'Keefe,Barry [ORCID]

  2. Author Address

    Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States., Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States., Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States., Curia India Pvt. Ltd (Formerly Albany Molecular Research), Hyderabad Research Centre, Hyderabad, Telangana 500078, India., Natural Products Branch, Development Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland 21702, United States.,
    1. Year: 2025
    2. Date: Jun 06
    3. Epub Date: 2025 06 06
  2. Journal: Journal of Medicinal Chemistry
  4. Type of Article: Article
  1. Abstract:

    Chimeric kinase J-PKAca represents a potential therapeutic target for fibrolamellar hepatocellular carcinoma (FLHCC). Structure-based design and screening were applied to improve the potency of the marine-derived kinase inhibitor aplithianine A targeting J-PKAca. Three classes of aplithianines (I, II, and III) including >150 analogs were synthesized, significantly improving biochemical IC50 values to the low nanomolar range. X-ray diffraction experiments confirmed that the class II aplithianines adopted a novel binding mode to J-PKAca by interacting with the DFG residue Asp239. The kinase selectivity profiles were assessed by kinome profiling. In vitro profiles of selected class II analogs were evaluated to determine compound solubility, protein binding, permeability, metabolism, and hERG binding. Selected aplithianine analogs inhibited intracellular phosphorylation of the peptide substrate CREB following stimulation of the J-PKAca fusion kinase in NIH/3T3 cells and exhibited antiproliferative/cytotoxic activities against select cancer cell lines from the NCI-60 cell panel at nanomolar concentrations.

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External Sources

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  2. DOI: 10.1021/acs.jmedchem.5c00649
  3. PMID: 40476486

Library Notes

  1. Fiscal Year: FY2024-2025
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