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Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-Like Mechanism of Action

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Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-Like Mechanism of Action [CANCER RESEARCH 55. 2325-2333, June 1 1995] Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action Daniel M. Bollag, Patricia A. McQueney, Jian Zhu, Otto Hensens, Lawrence Koupal, Jerrold Liesch, Michael Goetz, Elias Lazarides,1 and Catherine M. Woods2 Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486 ID. M. B., P. A. M., J. Z, E. L, C. WJ and Department of Natural Products Chemistry, Merck Research Laboratories, Kahway, New Jersey 07065 ¡O.H., L K., J. L, M. C.¡ ABSTRACT cellular processes as cell division, locomotion, and intracellular trans port (4). MTs are highly dynamic polar structures, with growth Tubulin polymerization into microtubules is a dynamic process, with favored at the plus end and shrinkage more prevalent at the minus end. the equilibrium between growth and shrinkage being essential for many cellular processes. The antineoplastic agent taxol hyperstabilizes However, both MT ends experience periods of growth and shrinkage, polymerized microtubules, leading to mitotic arrest and cytotoxicity in a phenomenon described as dynamic instability (5). In vertebrate proliferating cells. Using a sensitive filtration-calorimetric assay to cells, the centrosome acts as the major site of MT nucleation (micro- detect microtubule nucleating activity, we have identified epothilones tubule-organizing center) by lowering the critical concentration of A and B as compounds that possess all the biological effects of taxol tubulin required for polymerization and anchoring the minus ends of both in vitro and in cultured cells. The epothilones are equipotent and the resultant MTs (6, 7). exhibit kinetics similar to taxol in inducing tubulin polymerization into Taxol preferentially binds the polymeric MT form of tubulin in microtubules in vitro (filtration, light scattering, sedimentation, and a 1:1 stoichiometry with the aß-tubulin heterodimer subunits, with electron microscopy) and in producing enhanced microtubule stability and bundling in cultured cells. Furthermore, these 16-membered ma- a Ap of ~1 /AM(8). Taxol binding markedly reduces the rate of crolides are competitive inhibitors of [3H]taxol binding, exhibiting a aß-tubulin dissociation, hence augmenting and stabilizing the MT 50% inhibitory concentration almost identical to that of taxol in dis pool (9). In vitro taxol has also been shown to nucleate tubulin placement competition assays. Epothilones also cause cell cycle arrest polymerization into MTs, eliminating the requirement for GTP in at the G2-M transition leading to cytotoxicity, similar to taxol. In normal polymerization (2, 10). Within cells this effect is mani contrast to taxol, epothilones retain a much greater toxicity against fested by micromolar taxol levels overriding the centrosomal P-glycoprotein-expressing multiple drug resistant cells. Epothilones, microtubule-organizing center function and inducing the appearance therefore, represent a novel structural class of compounds, the first to of many short non-centrosomally linked bundles throughout the cyto be described since the original discovery of taxol, which not only mimic the biological effects of taxol but also appear to bind to the same plasm (11). In rapidly cycling cultured human cells, taxol induces a block microtubule-binding site as taxol. at the transition between G, and M phase (12). Recent studies have clearly indicated that it is this mitotic arrest rather than the disruption of interphase MT function which is the actual mechanism behind the anti INTRODUCTION neoplastic activity of taxol (13, 14). Taxol and taxotere are novel cancer chemotherapeutic agents that Although taxol has shown efficacy against refractive ovarian (15), stabilize cellular MTs.3 Taxol, a complex diterpene with a taxane ring metastatic breast (16), head and neck (17), melanoma (18), and lung system, was discovered in 1971 in a screen for anticancer activity (1). (19) cancer, its clinical usefulness is limited by its side effect profile Following the elucidation of the mechanism of action of taxol (2), (neutropenia, peripheral neuropathy, and alopecia) (20) and the fact clinical trials have established taxol as an anticancer agent with that its low solubility necessitates that taxol be delivered in Cremo- significant activity against various human solid tumors (3). With phor. Cremophor delivery in itself can affect cardiac function and earlier drug supply problems resolved, vigorous synthetic efforts cause severe hypersensitivity responses (20). Furthermore, taxol is a under way to modify the structure of taxol, and trials of taxol efficacy substrate for P-glycoprotein which pumps many cytotoxic compounds in combination therapy in progress, further improvements in taxane- out of MDR cells (21). Multiple drug resistance represents a major based chemotherapy are likely. Nevertheless, the complexity of the limitation of many cancer interventions. The complex taxane ring taxol structure presents a major obstacle to facile chemical modifica structure of taxol is not readily amenable to chemical manipulation to tion aimed at improving the solubility characteristics and side effect improve the therapeutic index and solubility properties of this class of profile of taxol. A novel class of drugs which stabilizes MTs might compounds. We therefore sought to screen for a different structural stimulate the development of more effective cancer chemotherapeu- class of compounds that would mimic the MT-stabilizing properties tics with this mechanism of action. of taxol. Microtubules are one of the fundamental structures comprising the Here we report that epothilones A and B, 16-membered macrolides, cytoskeleton of eukaryotic cells and are involved in such diverse mimic all the biological effects of taxol, both in vitro and in cultured cells. Independently, Hoefle et al. (22) have described epothilones A Received 1/11/95; accepted 4/5/95. and B as having antifungal and cytotoxic activity. Competition studies The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with reveal that epothilones act as competitive inhibitors of taxol binding to 18 U.S.C. Section 1734 solely to indicale this fact. MTs, consistent with the interpretation that they share the same 1 Present address: Astral, Inc., San Diego, CA 92121. 2 Present address: Alliance Pharmaceutical Corp., San Diego, CA 92121. MT-binding site and posses a similar MT affinity as taxol. Epothi 3The abbreviations used are: MT, microtubule(s); MDR, multiple drug resistance; lones appear to possess one advantage over taxol; namely, they exhibit MEM buffer, 100 mw 2-(/V-morpholiro)ethanesulfonic acid, pH 6.75-1 rriMethyleneglycol bis(ß-aminoethyl ether)-/V,JV,/V',A''-tetraacetic acid-1 mM MgCI2; CNS agar, cellulose- a much lower drop in potency compared to taxol against a multiple nitrate salts agar; GNS3 agar, glucose-nitrate salts agar; NMR, nuclear magnetic reso drug-resistant cell line. The epothilones represent the first class of nance; EC50, 50% effective concentration; TÚNEL, biotin-terminal deoxytransferase end compounds to be described in the two decades following the original labeling of nicked DNA; HRMS, high resolution mass spectrometry; HMQC, helero- discovery of taxol which mimic the MT-stabilizing effect of the nuclear multiple quantum coherence; HMBC, heteronuclear multiple bond connectivity; HR-EIMS, high resolution electron impact mass spectrometry. taxane ring structure. 2325 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1995 American Association for Cancer Research. EPOTHILONES. A NEW CLASS OF MT-STABILIZING AGENTS MATERIALS AND METHODS Purification and Identification of Epothilones Materials Bacterial Strains and Growth Media. The cellulose-degrading myxobac- terium, Sorangium cellitlosum strain SMP 44, was obtained from the culture Taxol and GTP were purchased from Sigma. Uranyl acetate was obtained collection of J. E. Peterson. Emporia State University, Emporia, KS, and was from Ernest F. Fullam, Inc. For immunofluorescence microscopy, anti-chick found to form bright orange fruiting body structures on media containing ß-tubulinmonoclonal (Amersham) and FITC-conjugated anti-mouse (Cappel) cellulose. The fruiting bodies of this strain were routinely preserved as air- antibodies were used. HeLa cervical epithelioid carcinoma cells and Hs578T dried preparations on sterile 6-mm paper disks. Primary cultivation was ac and Hs578Bst breast carcinoma and Rati cells were obtained from the Amer complished by inoculation of the dried fruiting bodies onto CNS agar and ican Type Culture Collection. The multiple drug-resistant human carcinoma incubating the medium at 27°Cfor 10-15 days. CNS agar contained (g/liter): cell line KBV-1 and its parental line, KB3-1, were provided by I. Pastan (23). KNO,, 0.5; Na2HPO4, 0.25; MgSO4-7H2O, 1.0; HEPES, 2.4; FeCl2, 0.01; Tubulin Purification Difco agar, 15.0. Before the medium was autoclaved, the pH was adjusted to 7.0-7.2 with dilute HCI. After solidification of the medium in sterile 90-mm Microtubule protein was purified from bovine brains essentially as de Petri dishes, sterile Whatman No. 1 filter paper was applied to the surface of scribed by Asnes and Wilson (24). Brains were rinsed in cold saline solution the agar. Dried fruiting bodies characteristically required an incubation period within l h of sacrifice. Whole brains were minced and homogenized with 500 of about
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