title: Triphenylbutanamines: kinesin spindle protein inhibitors with in vivo antitumor activity.
abstract: The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most potent C-trityl analogues exhibit K(i)(app) ≤ 10 nM and GI(50) ≈ 50 nM, comparable to results from the phase II clinical benchmark ispinesib. Crystallographic studies reveal that they adopt the same overall binding configuration as S-trityl analogues at an allosteric site formed by loop L5 of Eg5. Evaluation of their druglike properties reveals favorable profiles for future development and, in the clinical candidate ispinesib, moderate hERG and CYP inhibition. One triphenylbutanamine analogue and ispinesib possess very good bioavailability (51% and 45%, respectively), with the former showing in vivo antitumor growth activity in nude mice xenograft studies.
authors.affiliation: Molecular Motor Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, Scotland, UK. wangfang@moon.ibp.ac.cn
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: James A D
authors.initials: JA
authors.lastname: Good
authors.forename: Oliver
authors.initials: O
authors.lastname: Rath
authors.forename: Hung Yi Kristal
authors.initials: HY
authors.lastname: Kaan
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Sutcliffe
authors.forename: Simon P
authors.initials: SP
authors.lastname: Mackay
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002082:Butylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011487:Protein Conformation; D011799:Quinazolines / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001555:Benzene Derivatives; D002082:Butylamines; C470243:KIF11 protein, human; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins