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    UA62784; a Putative Inhibitor of CENP-E Kinesin-like Protein and its Effects on Human Pancreatic Cancer Cells

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    Author
    Henderson, Meredith C.
    Issue Date
    2008
    Keywords
    cancer
    pancreatic
    kinesin
    CENP-E
    DPC4
    Advisor
    Dorr, Robert T.
    Committee Chair
    Dorr, Robert T.
    
    Metadata
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    UA62784 is a novel fluorenone identified in a biologic screen of compounds that are selectively cytotoxic in DPC4 (deleted in pancreatic cancer)-deleted pancreatic cancer cells. We sought to determine the mechanism of action of UA62784, and discovered it to be a potent mitotic inhibitor. UA62784 affects the ATPase activity of the mitotic kinesin centromere protein E (CENP-E), but does not affect other known mitotic kinesins. This inhibition of ATPase activity is not caused by an inhibition of microtubule binding nor is it caused by a failure of the kinesin to translocate to the nucleus during mitosis. Despite the anti-cancer properties of this drug, UA62784 is relatively insoluble and is not suitable as a lead compound for further development.Once we determined the mechanism of action of UA62784, we sought to determine if analogs would demonstrate the same potent mitotic inhibition while also offering properties such as increased solubility. A small library of chemical analogs was generated wherein each compound was a slight variation of UA62784 (termed the DPC series). Several potential leads were identified which exhibited increased solubility and/or increased cytotoxic activity. When tested for CENP-E ATPase inhibition, some compounds were noted to inhibit other kinesins as well. We therefore created a screen where each of the DPC compounds was tested for activity in Eg5, CENP-E, MKLP-1, MCAK, and KIF3C kinesins. Within these data, there is a correlation between cellular IC50 and kinesin ATPase inhibition for CENP-E and MKLP-1. A few compounds emerged from these studies, including DPC046, which has a low cellular IC50 and inhibits all five kinesins to some degree. DPC046 was used in a mouse xenograft study to determine in vivo efficacy, but no significant tumor shrinkage was seen, likely due to solubility limitations affecting the amount of bioavailable compound.From these studies we conclude that the cytotoxic effects seen in UA62784 and its analogs are due, at least in part, to their inhibition of kinesin proteins. We demonstrate that compounds that inhibit CENP-E and other kinesin proteins hold promise in cytotoxically targeting pancreatic cancer cells. Further development is needed to optimize DPC046 compound solubility in order to increase in vivo efficacy.
    Type
    text
    Electronic Dissertation
    Degree Name
    PhD
    Degree Level
    doctoral
    Degree Program
    Cancer Biology
    Graduate College
    Degree Grantor
    University of Arizona
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