Topic
Epothilone
About: Epothilone is a research topic. Over the lifetime, 352 publications have been published within this topic receiving 13001 citations. The topic is also known as: epothilone.
Papers published on a yearly basis
Papers
Journal Article•
TL;DR: Efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol in both clinical efficacy and ease of use (i.e., less frequent treatment schedule and/or oral administration).
Abstract: BMS-247550, a novel epothilone derivative, is being developed by Bristol-Myers Squibb Company (BMS) as an anticancer agent for the treatment of patients with malignant tumors. BMS-247550 is a semisynthetic analogue of the natural product epothilone B and has a mode of action analogous to that of paclitaxel ( i.e. , microtubule stabilization). In vitro , it is twice as potent as paclitaxel in inducing tubulin polymerization. Like paclitaxel, BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at low nanomolar concentrations. Importantly, BMS-247550 retains its antineoplastic activity against human cancers that are naturally insensitive to paclitaxel or that have developed resistance to paclitaxel, both in vitro and in vivo . Tumors for which BMS-247550 demonstrated significant antitumor activity encompass both paclitaxel-sensitive and -refractory categories, i.e. , ( a ) paclitaxel-resistant: HCT116/VM46 colorectal (multidrug resistant), Pat-21 breast and Pat-7 ovarian carcinoma (clinical isolates; mechanisms of resistance not fully known), and A2780Tax ovarian carcinoma (tubulin mutation); ( b ) paclitaxel-insensitive: Pat-26 human pancreatic carcinoma (clinical isolate) and M5076 murine fibrosarcoma; and ( c ) paclitaxel sensitive: A2780 ovarian, LS174T, and HCT116 human colon carcinoma. In addition, BMS-247550 is p.o. efficacious against preclinical human tumor xenografts grown in immunocompromised mice or rats. Schedule optimization studies indicate that BMS-247550 is efficacious when administered frequently (every 2 days × 5) or intermittently (every 4 days × 3 or every 8 days × 2). These efficacy data demonstrate that BMS-247550 has the potential to surpass Taxol® in both clinical efficacy and ease of use ( i.e. , less frequent treatment schedule and/or oral administration).
509 citations
TL;DR: The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug-tubulin interactions that should assist in the rational design of agents targeting tubulin.
Abstract: The epothilones are naturally occurring antimitotic drugs that share with the taxanes a similar mechanism of action without apparent structural similarity. Although photoaffinity labeling and electron crystallographic studies have identified the taxane-binding site on β-tubulin, similar data are not available for epothilones. To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B. These epothilone-resistant sublines exhibit impaired epothilone- and taxane-driven tubulin polymerization caused by acquired β-tubulin mutations (β274Thr→Ile and β282Arg→Gln) located in the atomic model of αβ-tubulin near the taxane-binding site. Using molecular modeling, we investigated the conformational behavior of epothilone, which led to the identification of a common pharmacophore shared by taxanes and epothilones. Although two binding modes for the epothilones were predicted, one mode was identified as the preferred epothilone conformation as indicated by the activity of a potent pyridine-epothilone analogue. In addition, the structure–activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value. Finally, these pharmacophore and activity data from mutant cells were used to model the tubulin binding of sarcodictyins, a distinct class of microtubule stabilizers, which in contrast to taxanes and the epothilones interact preferentially with the mutant tubulins. The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug–tubulin interactions that should assist in the rational design of agents targeting tubulin.
504 citations
TL;DR: The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol and this heterologous expression system portends a plentiful supply of this important agent.
Abstract: The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading module, one nonribosomal peptide synthetase module, eight polyketide synthase modules, and a P450 epoxidase that converts desoxyepothilone into epothilone. Concomitant expression of these genes in the actinomycete Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent.
471 citations
TL;DR: The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-product synthesis and paves the way for the generation of large combinatorial libraries of these important molecules for biological screening.
Abstract: Epothilones A and B, two compounds that have been recently isolated from myxobacterium Sorangium cellulosum strain 90, have generated intense interest among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with microtubules and anticancer potential of these molecules. Like taxol, they exhibit cytotoxicity against tumour cells by inducing microtubule assembly and stabilization, even in taxol-resistant cell lines. Following the structural elucidation of these molecules by X-ray crystallography in 1996, several syntheses of epothilones A and B have been reported, indicative of the potential importance of these molecules in the cancer field. Here we report the first solid-phase synthesis of epothilone A, the total synthesis of epothilone B, and the generation of a small epothilone library. The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-product synthesis and, together with solution-phase synthesis of other epothilones, paves the way for the generation of large combinatorial libraries of these important molecules for biological screening.
443 citations
TL;DR: The future holds more promise for the development of more effective treatment for metastatic breast cancer with new developmental agents with improved specificity for tumour cells, and those with low susceptibility to common tumour-resistance mechanisms, such as ixabepilone.
364 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 2 |
| 2024 | 5 |
| 2023 | 14 |
| 2022 | 6 |
| 2021 | 6 |
| 2020 | 7 |