title: Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5.
abstract: The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM.
authors.affiliation: Institut de Biologie Structurale, 41, rue Jules Horowitz, 38027 Grenoble Cedex 01, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Debonis
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Skoufias
authors.forename: Rose-Laure
authors.initials: RL
authors.lastname: Indorato
authors.forename: François
authors.initials: F
authors.lastname: Liger
authors.forename: Bernard
authors.initials: B
authors.lastname: Marquet
authors.forename: Christian
authors.initials: C
authors.lastname: Laggner
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Frank
authors.initials: F
authors.lastname: Kozielski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008938:Mitosis; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; C470243:KIF11 protein, human; C003724:3-tritylthio-L-alanine; D016547:Kinesins; D003545:Cysteine