Recent Research Developments
- By Professor Craig Forsyth and his research group.
The phorboxazole natural products are among the most potent anti-cancer compounds discovered. The mode and mechanism of their anti-cancer action was initially established as being entirely distinct from all other known agents. Hence, the potential utility of phorboxazoles and derivatives as novel anti-cancer agents has spurred intense international research. The original total synthesis of the nano-scale natural product phorboxazole A, completed in Kolthoff Hall on February 13, 1998, coupled with subsequent improvements, and structure-activity studies have provided the material and knowledge base for the generation of fluorescently labeled phorboxazole probes for in vivo biophotonic studies. Phorboxazole binding proteins were isolated from a human cancer cell line using these probes, and their sequences and identities were determined via trypsin digestion and nano-LC ms-ms / proteomic studies. The proteomic hits were then verified by oncogenomic analyses and in vitro target validation studies using cloned proteins. These studies revealed that phorboxazole prevents the essential cell cycle progression protein cyclin dependent kinase 4 (cdk4) from translocating from the cytosol to the nucleus during the G1-S phase transition. It appears that the small molecule phorboxazole (MW ca. 1100 Da) induces a persistant (Ka ~10-7 – 10-9) association of cdk4 with cytosolic cytokeratin intermediate filaments. Although anticancer agents currently in clinical trials target cdk4 by occupying the ATP-binding site, sequestration of cdk4 upon cytoskeletal intermediary filaments is a novel mechanism of anticancer action that only the phorboxazoles elicit. This discovery offers obvious opportunities to control the spatial and temporal localization of cell growth regulatory proteins using synthetic small molecules.
Next scheduled update: March 29th , 2006.
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