Microtubule stabilizing agent

Bergstralh DT, Ting JP (2006) Microtubule stabilizing agents their molecular signaling consequences and the potential for enhancement by drug combination. Cancer Treat Rev 32 166-179... 

Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to progression were increased with combination therapy as compared with capecitabine alone. Adverse effects include myelosuppression, peripheral neuropathy, and myalgias/arthralgias. 

Chemical Synthesis and Biological Studies of the Epothilones - Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. 

Mooberry, S.L., RandaU-Hlubek, D.A., Leal, R.M., et al. (2004) Microtubule-stabilizing agents based on designed lauhmatide analogues. Proc. Natl. Acad. Sci. U. S. A., 101, 8803-8808. 

Goodin S. (2008) Ixabepilone A novel microtubule-stabilizing agent for the treatment of metastatic breast cancer. Am J Health Syst Pharm 65 2017-2026. 

Molnar 1, Schupp T, Ono M, et al. (2000) The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium ceUulosum So ce90. Chem. Biol. 7 97-109. 

D. C. Myles (2002). Emerging microtubule stabilizing agents for cancer chemotherapy. Annu. Rep. Med. Chem. 37 125. 

Kowalski RJ, Giannakakous P et al (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272 2534-2541... 

The first chapter focuses on the total synthesis of macrolide-based microtubules stabilizing agents and on SAR data thereof, which have not been covered in other... 

The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology. 

Keywords Antitumour drugs, Bioconfonner, Microtubule stabilizing agents, Paclitaxel... 

Biochemical Background on Microtubule Stabilizing Agents. What is a Microtubule Stabilizer ... 

On the other hand, from a thermodynamical point of view, a common mechanism for assembly induction can be proposed. All microtubule stabilizing agents bind tightly to the assembled form, while they do not bind with a measurable affinity to the dimeric tubulin [33], indicating that the taxane binding pocket is either not formed or not-completely formed in non-microtubular tubulin. 

However, since microtubule stabilizing agents will bind tightly to unoccupied sites, it is reasonable to assume that both mechanisms should work however, in this case the apparent critical concentration will saturate following Eq. (5) (as in Eq. 4) in the case where path 3b is followed the term ([Tub-Lig]+[Tub])[Mtb] should be replaced by ([Mtb-Lig] + [Mtb]) [Tub]) ... 

From the kinetics of ligand binding to microtubules we can obtain valuable information about the way paclitaxel microtubule stabilizing agents reach their binding site. They bind to an external binding site located in the pores of the microtubule wall from which they are totally or partially relocated to an inner luminal site. 

Peluroside A was the first microtubule stabilizing agent whose conformation has been determined bound to microtubules (those of Paclitaxel and Epothilone were determined in non-microtubular tubulin [5, 12, 38, 91]). In the bound state, the NMR data, assisted by molecular mechanics calculations and docking experiments, indicated that only one (that present in water, B) of the two major conformations existing in water solution is bound to microtubules (a-tubulin). A model of the binding mode to tubulin has also been proposed [27], involving the a-tubulin monomer, in contrast with paclitaxel, which binds to the p-monomcr. 

Canales A, Matesanz R, Gardner NM, Andreu JM, Paterson I, Diaz JF, Jimenez-Barbero J (2008) The bound conformation of microtubule-stabilizing agents (II) NMR insights on the bioactive 3D structure of discodermolide and dictyostatin. Chemistry (DOI 10.1002/chem.200800039)... 

The Tlibulin Binding Mode of Microtubule Stabilizing Agents Studied by Electron Crystallography... 

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