title: Structure-activity relationship and multidrug resistance study of new S-trityl-L-cysteine derivatives as inhibitors of Eg5.
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.
authors.affiliation: The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, Scotland, UK.
authors.forename: Hung Yi Kristal
authors.initials: HY
authors.lastname: Kaan
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Dominik
authors.initials: D
authors.lastname: Menger
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Ulaganathan
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tkocz
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Florence
authors.initials: F
authors.lastname: Popowycz
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; D014320:Triphenylmethyl Compounds; D000251:Adenosine Triphosphatases; D016547:Kinesins; D003545:Cysteine