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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In summary, the epothilones represent an important new family of anticancer agents, especially for patients who develop resistance to standard therapies. In this context, the new epothilone ixabepilone (IxempraTM) is viewed as an important advance in the treatment of breast cancer because of its relative lack of cross-resistance with commonly used therapeutic agents, including the taxanes. Ixabepilone (IxempraTM), which is approved and marketed in most parts of the world, is described in more detail below, along with one related agent, sagopilone (ZK219477; ZK-EPO), which reached Phase II clinical trials in glioblastoma but was not progressed.
Diagnosis and management of uterine serous carcinoma: current strategies and clinical challenges
Published in Expert Opinion on Orphan Drugs, 2020
Omar Najjar, Britt K. Erickson, Amanda N. Nickles-Fader
Targeted therapies have also addressed the challenge of platinum resistance in recurrent USC by targeting proteins such as AXL and tubulin-β-III. The AXL gene encodes a receptor tyrosine kinase that promotes cell migration and invasion. AXL is highly expressed in most USC tumors and has been associated with poorer survival outcomes and platinum resistance in USC [60]. The treatment of USC cell lines with BGB324, a small molecule inhibitor of AXL, increased the paclitaxel sensitivity of USC cell lines in vitro, enhancing paclitaxel accumulation in cells. In USC mouse xenograft models, combination treatment with paclitaxel and BGB324 inhibited tumor growth more effectively than paclitaxel alone. Similarly, the overexpression of tubulin-β-III in USC is a marker for poor survival and platinum resistance [108]. Epothilones are cytotoxic agents that inhibit cell division by interfering with tubulin function. USC cell lines overexpressing tubulin-β-III showed high resistance to paclitaxel and high sensitivity to epothilones [108].
Enhanced anti-proliferative efficacy of epothilone B loaded with Escherichia coli Nissle 1917 bacterial ghosts on the HeLa cells by mitochondrial pathway of apoptosis
Published in Drug Development and Industrial Pharmacy, 2018
Wenxing Zhu, Lujiang Hao, Xinli Liu, Orlando Borrás-Hidalgo, Yuyu Zhang
The epothilones produced by the myxobacterium Sorangium cellulosum constitute a new class of highly promising anti-cancer agents [1,2]. These agents belong to a 16-member family with ring macrolides combined with a methylthiazole side chain [3]. Epothilones bind to β-tubulin subunit of the αβ-tubulin dimer of microtubules, stabilize preformed microtubules and lead to aberrant spindle formation during mitosis with subsequent mitotic arrest and cell apoptosis [4,5]. The anti-cancer mechanism of epothilones was similar to paclitaxel, while the epothilones have better efficacy on paclitaxel-susceptible and paclitaxel-resistant cancer cells that display a multidrug-resistance phenotype due to overexpression of the P-glycoprotein (P-gp) efflux pump [6,7]. Epothilones, especially epothilone B (Epo B) and its derivatives, were shown to induce regression of various types of human cancers including glioma, colon, breast, lung, and ovarian carcinomas [8]. However, the systemic application of epothilones causes some toxic side effects, such as neutropenia, sensory neuropathy, diarrhea, nausea, fatigue, and vomiting [9,10]. In order to overcome or reduce these undesired effects and maintaining the drug potency, epothilones might be encapsulated into drug delivery vehicles to allow a site-specific targeting and prolong the drugs circulation time inside the body.
Recent developments with tau-based drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Khalid Iqbal, Fei Liu, Cheng-Xin Gong
Hyperphosphorylated tau induces neurotoxicity by disrupting the microtubule network of the affected neurons. Thus, one therapeutic approach is to stabilize the neuronal microtubule network by pharmacological treatment. Toward this goal, an octamer peptidergic compound called Davunetide, also known as NAP or AL-108, is a microtubule-stabilizing peptide subunit of activity-dependent neuroprotective protein. This peptide was tested by intranasal administration both in AD and PSP patients. While the compound showed no serious adverse effects, it did not show significant beneficial effect in Phase II or III [136]. In preclinical studies, two non-peptidergic small brain penetrant compounds, epothilone D and a newer more potent compound, dictyostatin, were found to be very promising in transgenic mouse models [137–139]. However, a human clinical trial on epothilone D, BMS341027/BMS-241027, was discontinued without any reported explanation by Bristol Meyers Squibb. TPI 287 is a tubulin binding and microtubule-stabilizing drug and is a synthetic derivative of the taxane diterpenoid drugs used for cancer therapy. Cortice Biosciences is conducting TPI 287 Phase I trials on AD and 4-repeat tauopathies, PSP/corticobasal degeneration.