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Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression
Jason P Holland1, Michael W Jones, Susan Cohrs
1Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Department of Radiology, Harvard Medical School, 55 Fruit St., White 427, Boston, MA 02114, USA. holland.jason@mgh.harvard.edu
Abstract:
Anti-mitotic anti-cancer drugs offer a potential platform for developing new radiotracers for imaging proliferation markers associated with the mitosis-phase of the cell-cycle. One interesting target is kinesin spindle protein (KSP)-an ATP-dependent motor protein that plays a vital role in bipolar spindle formation. In this work we synthesised a range of new fluorinated-quinazolinone compounds based on the structure of the clinical candidate KSP inhibitor, ispinesib, and investigated their properties in vitro as potential anti-mitotic agents targeting KSP expression. Anti-proliferation (MTT and BrdU) assays combined with additional studies including fluorescence-assisted cell sorting (FACS) analysis of cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Additional studies using confocal fluorescence microscopy showed that these compounds induce M-phase arrest via monoaster spindle formation. Structural studies revealed that compound 20-(R) is the most potent fluorinated-quinazolinone inhibitor of KSP and represents a suitable lead candidate for further studies on designing (18)F-radiolabelled agents for positron-emission tomography (PET).
Insights
New fluorinated-quinazolinone compounds targeting kinesin spindle protein (KSP) show potent anti-cancer activity. Compound 20-(R) is a promising lead for developing radiotracers for imaging cancer cell proliferation.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Anti-mitotic drugs are explored for cancer imaging radiotracer development.
- Kinesin spindle protein (KSP) is crucial for cell division and a target for anti-cancer agents.
Purpose of the Study:
- Synthesize novel fluorinated-quinazolinone compounds as KSP inhibitors.
- Evaluate their anti-mitotic potential and suitability for developing PET imaging agents.
Main Methods:
- Synthesis of fluorinated-quinazolinone derivatives based on ispinesib.
- In vitro anti-proliferation assays (MTT, BrdU).
- Cell-cycle analysis (FACS) and confocal fluorescence microscopy.
Main Results:
- Compounds demonstrated potent anti-proliferative effects in human cancer cell lines.
- Confirmed M-phase arrest via monoaster spindle formation.
- Compound 20-(R) identified as the most potent KSP inhibitor.
Conclusions:
- Fluorinated-quinazolinones are effective KSP inhibitors with anti-mitotic activity.
- Compound 20-(R) is a promising candidate for (18)F-radiolabeled PET imaging agent development.
