Novel Tubulin Binders With Efficacy Against Muti-Drug Resistant Tumor Cells

Julio C. Medina
Associate Director, Medicinal Chemistry
Tularik, Inc.



Microtubules are linear polymers of a - and b -tubulin heterodimers. They are a major component of the cytoskeleton of eukaryotic cells and play a crucial role in cell motility and mitosis. Microtubules are also the main target of important chemotherapeutic agents such as paclitaxel and vinblastine. However, the emergence of multi-drug resistance following initially successful chemotherapy is one of the major causes of treatment failure for these agents.

We have discovered a novel class of pentafluorophenyl-sulfonamides, typified by the clinical candidates T138067 and T900607, that inhibits the growth of a broad variety of tumor cell lines, including those with acquired resistant to paclitaxel, vinblastine and other chemotherapeutics. We have demonstrated that drug-resistant cells that develop their resistance from expression of p-glycoprotein (MDR-1), or the multidrug resistance-associated protein (MRP-1), shifting tubulin isotype patterns, or by mutations in the tubulin protein remain essentially sensitive to the growth inhibitory effects of T138067 and T900607.

We studied the mechanism of action of these novel compounds in order to understand how they maintain their efficacy against multi-drug resistant cells. It was discovered that these compounds undergo nucleophilic aromatic substitution by Cys-239 of b-tubulin, at the para fluorine atom of the pentafluorobenzene moiety. Here we present the structure activity relationship studies that lead to the selection of T138067 and T90607 as clinical candidates and discuss the evidence for their proposed mechanism of action.

References:

1. Medina, J. C.; Shan, B.; Beckmann, H.; Farrell, R. P.; Clark, D. L.; Learned, R. M.; Roche, D.; Li, A.; Baichwal, V.; Case, C.; Baeurle, P.; Rosen, T.; Jaen, J. C. "Novel Antineoplastic Agents with Efficacy Against Multidrug Resistant Tumor Cells" Bioorg. Med. Chem. Lett., 1998, 8,19, 2653.

2. Medina, J. C.; Daniel R.; Shan B.; Learned R. M.; Frankmoelle, W. P.; Clark, D. L.; Rosen, T.; Juan J. C. "Novel Halogenated Sulfonamides Inhibit The Growth of Multidrug Resistant MCF-7/ADR Cancer Cells" Bioorg. Med. Chem. Lett. , 1999, 9, 1843-1846.

3. Shan, B.; Medina, J. C.; Santha, E.; Frankmoelle, W. P.; Chou, T. C.; Learned, R. M.; Narbut, M. R.; Scott, D.; Wu, P.; Jaen, J. C.; Rosen, T.; Timmermans, P. B. M. W. M.; Beckmann, H. "Selective, covalent modification of b-tubulin residue Cys-239 by T138067, an antitumoragent with in vivo efficacy against multidrug-resistant tumors" Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 5686.

4. Frankmoelle, W.P.; Medina, J.C.; Shan, B.; Narbut, M.R.; Beckmann, H. "Glutathione S-transferase metabolism of the antineoplastic pentafluorophenylsulfonamide in tissue culture and mice" Drug. Metab. Dispos., 2000, 28, 951.