2. Academic Validation
  3. Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors

Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors

  • J Med Chem. 2025 Jun 26;68(12):12756-12785. doi: 10.1021/acs.jmedchem.5c00649.
Lin Du 1,  Brice A P Wilson 1,  William J Moore 2,  Masoumeh Dalilian 1,  Shilpa R Shenoy 1,  Ning Li 3,  Juliana A Martinez Fiesco 3,  Ji-Yeon Hwang 1,  Emily A Smith 1,  Antony Wamiru 1,  Ekaterina I Goncharova 1 4,  Astrid Alvarez de la Cruz 3,  Karunakar Pagadala 5,  Harish K Piswa 5,  Venukumar Patteti 5,  Veera P Jampana 5,  Prasad Manepalli 5,  Ravi Nimmala 5,  Narender R Marri 5,  Mahendar Gunuguntla 5,  Jakkidi J Reddy 5,  John S Schneekloth Jr 2,  Ping Zhang 3,  Barry R O'Keefe 1 6
Affiliations

Affiliations

  • 1 Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
  • 2 Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
  • 3 Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.
  • 4 Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.
  • 5 Curia India Pvt. Ltd (Formerly Albany Molecular Research), Hyderabad Research Centre, Hyderabad, Telangana 500078, India.
  • 6 Natural Products Branch, Development Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland 21702, United States.
PMID: 40476486 DOI: 10.1021/acs.jmedchem.5c00649
Abstract

Chimeric kinase J-PKAcα 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-PKAcα. 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-PKAcα 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-PKAcα 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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-176532
    PKA Inhibitor
    PKA