Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors
- Bei Shan*,†,
- Julio C. Medina*,†,
- Edit Santha*,
- Walter P. Frankmoelle*,
- Ting-C. Chou‡,
- Robert M. Learned*,
- Mathew R. Narbut*,
- Dean Stott*,
- Pengguang Wu*,
- Juan C. Jaen*,
- Terry Rosen*,
- Pieter B. M. W. M. Timmermans*, and
- Holger Beckmann*,§
- *Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080; and ‡Laboratory of Biochemical Pharmacology and Preclinical Pharmacology Core Facility, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021
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Communicated by Daniel E. Koshland, University of California, Berkeley, CA (received for review November 1, 1998)
Abstract
Microtubules are linear polymers of α- and β-tubulin heterodimers and are the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis. Here we describe a synthetic compound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), which covalently and selectively modifies the β1, β2, and β4 isotypes of β-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in shape, indicating a collapse of the cytoskeleton, and show an increase in chromosomal ploidy. Subsequently, these cells undergo apoptosis. Furthermore, T138067 exhibits cytotoxicity against tumor cell lines that exhibit substantial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive and multidrug-resistant human tumor xenografts in athymic nude mice. These observations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.
