ECB-ART-42148
Bioorg Med Chem
2011 Sep 15;1918:5446-53. doi: 10.1016/j.bmc.2011.07.054.
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Synthesis and characterization of tritylthioethanamine derivatives with potent KSP inhibitory activity.
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
.
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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.
???displayArticle.pubmedLink??? 21855351
???displayArticle.pmcLink??? PMC3171608
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P20 RR016480 NCRR NIH HHS , P20 RR016480-08 NCRR NIH HHS , P20 RR16480 NCRR NIH HHS , Howard Hughes Medical Institute
Genes referenced: LOC115919910
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