Abstract
A series of diaryl- and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of >3 μM were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.
- SAR, structure-activity relationship
- DPC-4, deleted in pancreas cancer locus 4
- PC, pancreatic cancer
- SMAD-4, mothers against DPP homologs-4
- Eg5, mitotic kinesin-5
- CENP-E, centromere binding protein E
- MKLP-1, mitotic kinesin-like protein-1
- MCAK, mitotic centromere-associated kinesin
- KIF3C, kinesin family member-3
- TrkB, tyrosine receptor kinase B
- IRAK-4, interleukin-1 receptor-associated kinase-4
- PIM-1, proto-oncogene Pim-1
- PDGFR, platelet-derived growth factor receptor
- SCID, severe combined immunodeficiency
- STR, short tandem repeat
- PCR, polymerase chain reaction
- DMSO, dimethyl sulfoxide
- PI, propidium iodide
- AUC, area under the curve
- LC, liquid chromatography
- MS, mass spectrometry
- RED, rapid equilibrium dialysis
- EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
- DIEA, N,N-diisopropylethylamine
- DCM, dichloromethane
- DMF, N,N-dimethylformamide.
Footnotes
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This work was funded by the National Institutes of Health National Cancer Institute [Grant CA109552] (to D. D. Von Hoff of the Translational Genomics Research Institute, Phoenix, AZ).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.156406
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ABBREVIATIONS:
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A.Y.S. and M.C.H. contributed equally to this work.
- Received May 19, 2009.
- Accepted August 3, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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