Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors
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 IC<sub>50</sub> 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. <i>In vitro</i> 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.
Authors
- Shilpa R. Shenoy
- Ekaterina I. Goncharova
- Antony Wamiru
- Venukumar Patteti
- Ji-Yeon Hwang
- J. Janardhan Reddy
- Masoumeh Dalilian
- Juliana A. Martinez Fiesco (ORCID: https://orcid.org/0000-0002-2396-0974)
- John S. Schneekloth (ORCID: https://orcid.org/0000-0001-7459-783X)
- Barry R. O’Keefe (ORCID: https://orcid.org/0000-0003-0772-4856)
- Ping Zhang (ORCID: https://orcid.org/0000-0002-0340-281X)
- Emily A. Smith (ORCID: https://orcid.org/0000-0001-8869-2336)
- William Moore (ORCID: https://orcid.org/0000-0002-0929-2228)
- Lin Du (ORCID: https://orcid.org/0000-0001-8751-4482)
- Brice A. P. Wilson (ORCID: https://orcid.org/0000-0001-8988-1964)
- Mahendar Reddy Gunuguntla
- Ning Li (ORCID: https://orcid.org/0000-0002-6224-1809)
- Astrid Alvarez de la Cruz (ORCID: https://orcid.org/0009-0003-5787-8519)
- Karunakar Pagadala
- Harish K. Piswa
- Veera P. Jampana
- Prasad Manepalli
- Ravi Nimmala
- Narender R. Marri
Institutions
- Target (United States) (US)
- Frederick National Laboratory for Cancer Research (US)
- BioAxis DNA Research Centre (India) (IN)
- National Cancer Institute (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00649
- Citations
- 1
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 1.52