Structure-activity relationship and multidrug resistance study of new S-trityl-l-cysteine derivatives as inhibitors of Eg5

• Verfasst von: Kaan, Hung Yi Kristal [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Verfasst von: Menger, Dominic [VerfasserIn]
• Verfasst von: Ulaganathan, Venkatasubramanian [VerfasserIn]
• Verfasst von: Tkocz, Katarzyna [VerfasserIn]
• Verfasst von: Laggner, Christian [VerfasserIn]
• Verfasst von: Popowycz, Florence [VerfasserIn]
• Verfasst von: Joseph, Benoît [VerfasserIn]
• Verfasst von: Kozielski, Frank [VerfasserIn]
• Titel: Structure-activity relationship and multidrug resistance study of new S-trityl-l-cysteine derivatives as inhibitors of Eg5
• Verf.angabe: Hung Yi Kristal Kaan, Johanna Weiss, Dominik Menger, Venkatasubramanian Ulaganathan, Katarzyna Tkocz, Christian Laggner, Florence Popowycz, Benoît Joseph, and Frank Kozielski
• E-Jahr: 2011
• Jahr: February 23, 2011
• Umfang: 11 S.
• Fussnoten: Gesehen am 30.06.2022
• Titel Quelle: Enthalten in: Journal of medicinal chemistry
• Ort Quelle: Washington, DC : ACS, 1959
• Jahr Quelle: 2011
• Band/Heft Quelle: 54(2011), 6, Seite 1576-1586
• ISSN Quelle: 1520-4804
• DOI: doi:10.1021/jm100991m
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1808714083

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.