Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors

Microtubules are linear polymers of alpha- and P-tubulin heterodimers and a re the major constituents of mitotic spindles, which are essential for the separation of chromosomes during mitosis, Here ne describe a synthetic comp ound, 2-fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene (T138067), w hich covalently and selectively modifies the beta(1), beta(2) and beta(4) i sotypes of beta-tubulin at a conserved cysteine residue, thereby disrupting microtubule polymerization. Cells exposed to T138067 become altered in sha pe, indicating a collapse of the cytoskeleton, and show an increase in chro mosomal ploidy, Subsequently, these cells undergo apoptosis. Furthermore, T 138067 exhibits cytotoxicity against tumor cell lines that exhibit substant ial resistance to vinblastine, paclitaxel, doxorubicin, and actinomycin D. T138067 is also equally efficacious in inhibiting the growth of sensitive a nd multidrug-resistant human tumor xenografts in athymic nude mice. These o bservations suggest that T138067 may be clinically useful for the treatment of multidrug-resistant tumors.