Document Report Card
Basic Information
ID: ALA1817631
Journal: Bioorg Med Chem
Title: Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.
Authors: Rodriguez D, Ramesh C, Henson LH, Wilmeth L, Bryant BK, Kadavakollu S, Hirsch R, Montoya J, Howell PR, George JM, Alexander D, Johnson DL, Arterburn JB, Shuster CB.
Abstract: 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.
CiteXplore: 21855351