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Identification of quinones as novel PIM1 kinase inhibitors
Richard L Schroeder1, Navneet Goyal1, Melyssa Bratton2
1Department of Chemistry, Xavier University of Louisiana, 1, Drexel Dr., New Orleans, LA 70125, USA.
Abstract:
PIM1 is a proto-oncogene encoding the serine/threonine PIM1 kinase. PIM1 kinase plays important roles in regulating aspects of cell cycle progression, apoptosis resistance, and has been implicated in the development of such malignancies as prostate cancer and acute myeloid leukemia among others. Knockout of PIM1 kinase in mice has been shown to be non-lethal without any obvious phenotypic changes, making it an attractive therapeutic target. Our investigation of anthraquinones as kinase inhibitors revealed a series of quinone analogs showing high selectivity for inhibition of the PIM kinases. Molecular modeling studies were used to identify key interactions and binding poses of these compounds within the PIM1 binding pocket. Compounds 1, 4, 7 and 9 inhibited the growth of DU-145 prostate cancer cell lines with a potency of 8.21μM, 4.06μM, 3.21μM and 2.02μM.
Insights
Anthraquinones selectively inhibit PIM kinases, crucial in cancer development. Specific compounds effectively inhibited prostate cancer cell growth, offering a promising therapeutic strategy for PIM1-driven malignancies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- PIM1 kinase, a proto-oncogene, regulates cell cycle and apoptosis resistance.
- PIM1 kinase is implicated in malignancies like prostate cancer and acute myeloid leukemia.
- PIM1 kinase is a potential therapeutic target due to non-lethal knockout phenotypes in mice.
Purpose of the Study:
- To investigate anthraquinones as selective PIM kinase inhibitors.
- To identify specific quinone analogs with potent PIM kinase inhibitory activity.
- To explore the binding interactions of these inhibitors within the PIM1 kinase active site.
Main Methods:
- Screening of anthraquinone analogs for PIM kinase inhibition.
- Molecular modeling to elucidate binding poses and key interactions.
- In vitro assessment of compound efficacy against prostate cancer cell lines.
Main Results:
- A series of quinone analogs demonstrated high selectivity for PIM kinase inhibition.
- Molecular modeling identified key binding interactions within the PIM1 pocket.
- Compounds 1, 4, 7, and 9 potently inhibited DU-145 prostate cancer cell growth (2.02–8.21 μM).
Conclusions:
- Anthraquinones represent a promising class of selective PIM kinase inhibitors.
- The identified compounds show potential for therapeutic development against PIM1-driven cancers.
- Further investigation into these analogs could lead to novel cancer treatments.
