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Structure-Activity Relationship and Multidrug Resistance Study of New S-trityl-L-Cysteine Derivatives As Inhibitors of Eg5†

DOI: 10.1021/jm100991m DOI Help
PMID: 21344920 PMID Help

Authors: Kristal Kaan (The Beatson Institute for Cancer Research) , Johanna Weiss (University Hospital Heidelberg) , Dominik Menger (University Hospital Heidelberg) , Venkat Ulaganathan (Beatson Institute for Cancer Research) , Katarzyna Tkocz (Beatson Institute for Cancer Research) , Christian Laggner (University of Innsbruck) , Florence Popowycz (Université de Lyon) , Benoit Joseph (Université de Lyon) , Frank Kozielski (The Beatson Institute for Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 54 (6)

State: Published (Approved)
Published: February 2011

Abstract: The mitotic spindle is a validated target for cancer chemotherapy. Drugs such as taxanes and vinca alkaloids specifically target microtubules and cause the mitotic spindle to collapse. However, toxicity and resistance are problems associated with these drugs. Thus, alternative approaches to inhibiting the mitotic spindle are being pursued. These include targeting Eg5, a human kinesin involved in the formation of the bipolar spindle. We previously identified S-trityl-l-cysteine (STLC) as a potent allosteric inhibitor of Eg5. Here, we report the synthesis of a new series of STLC-like compounds with in vitro inhibition in the low nanomolar range. We also performed a multidrug resistance study in cell lines overexpressing P-glycoprotein and showed that some of these inhibitors may have the potential to overcome susceptibility to this efflux pump. Finally, we performed molecular docking of the compounds and determined the structures of two Eg5−inhibitor complexes to explain the structure−activity relationship of these compounds.

Journal Keywords: Animals; Antineoplastic; Cell; Cell; Crystallography; X-Ray; Cysteine; Dogs; Drug; Drug; Multiple; Drug; Neoplasm; Epithelial; Humans; Kinesin; Models; Molecular; Stereoisomerism; Structure-Activity; Trityl Compounds

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography