Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity
2011
Rodriguez, Delany | Ramesh, Chinnasamy | Henson, Lauren H. | Wilmeth, Lori | Bryant, Bj K. | Kadavakollu, Samuel | Hirsch, Rebecca | Montoya, Johnelle | Howell, Porsha R. | George, Jon M. | Alexander, David | Johnson, Dennis L. | Arterburn, Jeffrey B. | Shuster, Charles B.
Assembly of a bipolar mitotic spindle requires the action of class 5 kinesins, and inhibition or depletion of this motor results in mitotic arrest and apoptosis. S-Trityl-l-cysteine is an allosteric inhibitor of vertebrate Kinesin Spindle Protein (KSP) that has generated considerable interest due to its anti-cancer properties, however, poor pharmacological properties have limited the use of this compound. We have modified the triphenylmethyl and cysteine groups, guided by biochemical and cell-based assays, to yield new cysteinol and cysteamine derivatives with increased inhibitory activity, greater efficacy in model systems, and significantly enhanced potency against the NCI60 tumor panel. These results reveal a promising new class of conformationally-flexible small molecules as allosteric KSP inhibitors for use as research tools, with activities that provide impetus for further development as anti-tumor agents.
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