title: Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol.
abstract: Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.
authors.affiliation: The Beatson Institute for Cancer Research, Garscube Estate, Bearsden, Glasgow, Scotland, UK.
authors.forename: Hung Yi Kristal
authors.initials: HY
authors.lastname: Kaan
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Ulaganathan
authors.forename: Oliver
authors.initials: O
authors.lastname: Rath
authors.forename: Hana
authors.initials: H
authors.lastname: Prokopcová
authors.forename: Doris
authors.initials: D
authors.lastname: Dallinger
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Kappe
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D050256:Antimitotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D018432:Drug Resistance, Multiple; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050256:Antimitotic Agents; C470243:KIF11 protein, human; D011743:Pyrimidines; D011799:Quinazolines; D013871:Thiones; C518969:dimethylenastron; C518968:enastron; C551950:fluorastrol; D016547:Kinesins