[Proceedings of the 11th NCI · EORTC · AACR Symposium]
Copyright © 2000 Stichting NCI-EORTC Symposium on New Drugs in Cancer Therapy
Published by the AACR.
139 T900607: Design and evaluation of a second-generation irreversible binder of -tubulin. Houze, Jonathan; Gergely, Joshua; Medina, Julio; Beckmann, Holger; Baichwal, Vijay; Roche, Daniel; Thoolen, Martin; Schwendner, Susan; Hoffman, Laura; Dimaio, Heather. Tularik Inc. Two Corporate Dr., S. San Francisco, CA 94080.
T138067 is an irreversible binder of -tubulin which shows potent activity in many murine models of human cancer. Clinical evaluation of T138067 was initiated in 1998. At the time, it was decided to continue SAR studies on the N-aryl-pentafluorophenylsulfonamides with the aim of identifying other compounds in the series which could display improved potency, efficacy and/or safety. Previous SAR studies had shown that activity in this series was dependent on the reactivity of the pentafluorophenylsulfonyl ring, therefore the current series of compounds mostly focuses on changes in the anilino portion of the molecule. These studies have led to the identification of a second-generation antitumor agent designated T900607 which incorporates chemical functionality which prevents the compound from crossing the blood-brain barrier. T900607 shows a broad array of cytotoxic activity (evaluated in the NCI panel of 60 tumor cell lines) as well as efficacy in the MX-1 human tumor xenograft model. The insensitivity to the MDR phenotype displayed by T067 is maintained by T900607 as shown by an identical TGI (concentration at which total growth inhibition occurs in the Alamar Blue metabolic dye assay) value of 150 nM versus both HeLa cells and MDR-positive MCF-7/ADR cells. Because of its decreased lipophilicity relative to T138067, T900607 displays an altered tissue distribution profile, primarily in terms of CNS permeability. Tumor and brain tissue from T138067 treated mouse models show extensive covalent modification of tubulin, whereas only tissue from the tumor and not the brain shows tubulin modification with T900607. Due to its promising activity, T900607 has recently entered phase I clinical evaluation |
