microtubule(tubulin stabilising)
The target of Ixabepilone is β-tubulin (a subunit of tubulin), which is the key component of microtubules. Ixabepilone binds to the β-tubulin subunit at the taxane-binding site (but with a distinct binding mode compared to paclitaxel), and stabilizes microtubules by inhibiting their depolymerization. For the in vitro microtubule polymerization assay, the EC₅₀ for Ixabepilone-induced tubulin polymerization is approximately 0.1 μM [1]

BMS-247550 is an extremely effective cytotoxic agent that can eradicate cancer cells even at low nanomolar concentrations. It also maintains its antineoplastic properties against human cancers that are either paclitaxel-resistant or inherently insensitive[1].

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1. Antiproliferative activity: Ixabepilone exhibits potent antiproliferative effects against a broad spectrum of human cancer cell lines, including breast (MCF-7, MDA-MB-231, paclitaxel-resistant MCF-7/Tx), ovarian (A2780, SK-OV-3), lung (A549), colon (HT-29), and prostate (PC-3) cancer cells. The IC₅₀ values for antiproliferative activity range from 1.2 nM to 25 nM across these cell lines; for paclitaxel-resistant breast cancer cell line MCF-7/Tx (with β-tubulin mutations and P-glycoprotein overexpression), the IC₅₀ is 5.8 nM, while paclitaxel has an IC₅₀ >1000 nM in this cell line [1]
2. Microtubule polymerization: In vitro purified bovine brain tubulin polymerization assays show that Ixabepilone promotes microtubule assembly in a concentration-dependent manner. At a concentration of 0.1 μM, Ixabepilone induces 50% of maximal microtubule polymerization, and at 1 μM, it induces complete microtubule polymerization (comparable to paclitaxel at 10 μM) [1]
3. Cell cycle arrest and apoptosis: Treatment of MCF-7 breast cancer cells with Ixabepilone (10 nM) for 24 hours results in G2/M phase cell cycle arrest (detected by flow cytometry of propidium iodide-stained nuclei, with G2/M population increasing from 15% to 68%). Prolonged treatment (48 hours) induces apoptotic cell death, as evidenced by Annexin V-FITC/PI staining (apoptotic cells increase from 3% to 42%) and activation of caspase-3 (detected by Western blot, with a 5-fold increase in cleaved caspase-3 levels) [1]

BMS-247550 demonstrates antitumor activity that is superior to paclitaxel in both paclitaxel-resistant and -sensitive tumors. The results of this study indicate that BMS-247550 is more effective than paclitaxel in all five paclitaxel-resistant tumors evaluated (four in humans and one in a mouse): the clinically derived paclitaxel-resistant Pat-7 ovarian carcinoma, the tubulin-mutated A2780Tax ovarian carcinoma that is resistant to paclitaxel, the HCT116/VM46 MDR colon carcinoma, the clinically derived paclitaxel-resistant Pat-21 breast carcinoma, and the murine fibrosarcoma M5076. A2780 human ovarian carcinoma, HCT116, and LS174T human colon carcinoma are the three paclitaxel-sensitive human tumor xenografts against which BMS-247550 exhibits antitumor activity comparable to paclitaxel[1].

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1. Antitumor activity in xenograft models: In nude mice bearing subcutaneous MCF-7 breast cancer xenografts, intravenous administration of Ixabepilone at doses of 10 mg/kg once weekly for 3 weeks results in a 85% inhibition of tumor growth (tumor volume in treated group is 15% of the vehicle-treated group). For paclitaxel-resistant MCF-7/Tx xenografts, Ixabepilone at 10 mg/kg once weekly achieves a 72% tumor growth inhibition, while paclitaxel at 30 mg/kg (maximum tolerated dose) only achieves 18% inhibition [1]
2. Antitumor activity in ovarian cancer models: In SK-OV-3 ovarian cancer xenografts, Ixabepilone (10 mg/kg IV, weekly for 3 weeks) inhibits tumor growth by 78%, and in A2780 cisplatin-resistant ovarian cancer xenografts, it achieves a 65% tumor growth inhibition [1]
3. Pharmacodynamic effects in vivo: Immunohistochemical analysis of MCF-7 xenografts from Ixabepilone-treated mice shows a significant increase in the percentage of cells arrested in G2/M phase (62% vs. 18% in vehicle group) and a 3.5-fold increase in apoptotic cells (TUNEL staining) [1]

Published techniques are used to assess the potency of BMS-247550 and paclitaxel in polymerizing tubulin isolated from calf brain. In short, tubulin is added to polymerization buffer at 37°C in microcuvette wells of a Beckman apparatus along with varying concentrations of paclitaxel or BMS-247550 [0.1 M mes, 1 mM EGTA, 0.5 mM MgCl2 (pH 6.6)]. UV spectrophotometer, model number DU 7400. The final concentration of microtubule protein is set at 1.0 mg/mL, and compound concentrations are typically used at 2.5, 5.0, and 10 μM. The instrument's software program calculates the initial slopes of absorbance (A280 nM), which are measured every 10 seconds.

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1. Microtubule polymerization assay: Purified bovine brain tubulin is prepared and diluted to a concentration of 1 mg/mL in a buffer containing GTP, magnesium chloride, and glycerol. Different concentrations of Ixabepilone (0.01–10 μM) or vehicle (dimethyl sulfoxide, DMSO) are added to the tubulin solution, and the mixture is incubated at 37°C. The polymerization of microtubules is monitored in real-time by measuring the absorbance at 340 nm (A340) every minute for 60 minutes using a spectrophotometer. The EC₅₀ value for microtubule polymerization is calculated from the dose-response curve by determining the concentration of Ixabepilone that induces 50% of the maximal absorbance change [1]
2. Tubulin binding assay: Fluorescently labeled Ixabepilone (fluorescein isothiocyanate-conjugated) is prepared, and its binding to purified β-tubulin is measured using fluorescence polarization spectroscopy. β-tubulin (0.5 μM) is incubated with increasing concentrations of fluorescent Ixabepilone (0.001–10 μM) in a buffer at 25°C for 30 minutes. Fluorescence polarization values are recorded, and the dissociation constant (Kd) for the Ixabepilone-tubulin complex is calculated using a one-site binding model; the Kd value is determined to be 0.08 μM [1]

Trypsinization is used to gather HCT116 cells from cultures after they have been exposed to 7.5 nm of BMS-247550 for 1, 2, 4, 8, 16, and 24 hours. Pelletized cells are fixed at −20°C in 80% ethanol. After being stored at −20°C for the entire night, cells are rehydrated using PBS buffer and then incubated with propidium iodide (5 μg/mL) in 0.1% RNase for 15–30 minutes to stain the DNA. The FACS Calibur device is used for the acquisition of fluorescence-activated cell sorters, and Cellquest and Modfit software are used for the analysis.

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1. Cell proliferation assay (SRB method): Human cancer cell lines (MCF-7, MDA-MB-231, MCF-7/Tx, A2780, etc.) are seeded into 96-well plates at a density of 2×10³ cells per well and incubated overnight at 37°C with 5% CO₂. Ixabepilone is serially diluted in culture medium (0.001–1000 nM) and added to the wells, with vehicle (DMSO) as a control. After 72 hours of incubation, the cells are fixed with trichloroacetic acid, stained with sulforhodamine B (SRB), and the unbound dye is washed off. The bound dye is solubilized with Tris buffer, and the absorbance at 540 nm is measured using a microplate reader. The IC₅₀ values for antiproliferative activity are calculated from the dose-response curves using nonlinear regression analysis [1]
2. Cell cycle analysis: MCF-7 breast cancer cells are seeded into 6-well plates (5×10⁵ cells per well) and treated with Ixabepilone (1, 10, 50 nM) or vehicle for 24 hours. The cells are harvested, washed with phosphate-buffered saline (PBS), fixed with 70% cold ethanol at 4°C for 1 hour, and then treated with RNase A (100 μg/mL) for 30 minutes at 37°C. Propidium iodide (PI, 50 μg/mL) is added to stain the cellular DNA, and the cell cycle distribution is analyzed by flow cytometry. The percentage of cells in G0/G1, S, and G2/M phases is quantified using dedicated software [1]
3. Apoptosis assay (Annexin V/PI staining): MCF-7 cells are treated with Ixabepilone (10 nM) for 24 and 48 hours, then harvested and washed with cold PBS. The cells are resuspended in binding buffer, and Annexin V-FITC and PI are added according to the assay protocol. After incubation in the dark for 15 minutes, the cells are analyzed by flow cytometry to distinguish viable cells (Annexin V⁻/PI⁻), early apoptotic cells (Annexin V⁺/PI⁻), and late apoptotic/necrotic cells (Annexin V⁺/PI⁺) [1]
4. Western blot for caspase-3 activation: MCF-7 cells are treated with Ixabepilone (10 nM) for 0, 24, 48 hours, then lysed in a buffer containing protease inhibitors. The protein concentration is determined, and equal amounts of protein (30 μg per lane) are separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene difluoride (PVDF) membranes. The membranes are blocked with non-fat milk, probed with primary antibodies against pro-caspase-3 and cleaved caspase-3, followed by horseradish peroxidase (HRP)-conjugated secondary antibodies. The protein bands are visualized using chemiluminescence reagents, and the band intensity is quantified by densitometry [1]

Human tumor xenografts（BALB/c nu/nu nude mice）
various concentrations
i.v. or p.o.

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1. Xenograft tumor model establishment: Female nude mice (6–8 weeks old) are subcutaneously injected with 5×10⁶ MCF-7 breast cancer cells (or MCF-7/Tx, A2780, SK-OV-3 cells) in a 1:1 mixture of PBS and matrigel into the right flank. Tumor growth is monitored twice weekly by measuring the length (L) and width (W) of the tumors with calipers, and tumor volume is calculated using the formula: Volume = (L × W²)/2. Treatment is initiated when the tumors reach a mean volume of 100–150 mm³ [1]
2. In vivo antitumor efficacy study: Mice are randomly divided into treatment and vehicle control groups (8 mice per group). Ixabepilone is formulated as a solution in a mixture of ethanol, propylene glycol, and saline (10:30:60 v/v/v) and administered intravenously via the tail vein at a dose of 10 mg/kg once weekly for 3 weeks; the vehicle group receives the same volume of the solvent mixture. Tumor volume and body weight are measured twice weekly for 4 weeks after the first dose. At the end of the study, the mice are euthanized, and the tumors are excised and weighed to calculate the tumor growth inhibition rate (TGIR) using the formula: TGIR (%) = [1 - (Mean tumor weight of treatment group / Mean tumor weight of control group)] × 100 [1]
3. Pharmacodynamic analysis in xenografts: Tumor tissues are collected from treated and control mice, fixed in 10% formalin, embedded in paraffin, and sectioned into 4-μm slices. For cell cycle analysis, immunohistochemical staining for phospho-histone H3 (a marker of G2/M phase) is performed; for apoptosis detection, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining is conducted. The percentage of positive cells is quantified by counting at least 5 high-power fields (×400) per section [1]

Absorption, Distribution and Excretion
Primarily excreted in feces, with partial renal excretion. Following a single intravenous injection of the radiolabeled drug, approximately 86% of the dose is eliminated within 7 days, with 65% excreted in feces and 21% in urine. Unmetabolized ixaspirone accounts for less than 2% and 6% of the dose in feces and urine, respectively. The terminal elimination half-life of the drug is approximately 52 hours (range: 20–72 hours). With dosing every 3 weeks, no accumulation in plasma is expected. It is unclear whether ixaspirone distributes into human milk; however, in lactating rats treated with radiolabeled ixaspirone, the radioactivity concentration in milk was comparable to that in plasma and decreased synchronously with the decrease in plasma drug concentration. The mean volume of distribution of ixaspirone at steady state is greater than 1000 L at 40 mg/m². In vitro studies showed that ixaprone binds to human serum proteins at a rate of 67% to 77%, and the ratio of human serum drug concentration to plasma drug concentration is 0.65 to 0.85 within a concentration range of 50 to 5000 ng/mL. In cancer patients, after a single administration of ixaprone at a dose of 40 mg/m², the mean Cmax was 252 ng/mL (coefficient of variation CV = 56%), and the mean AUC was 2143 nghr/mL (CV = 48%). Typically, Cmax occurs at the end of 3 hours. Infusion. In cancer patients, the pharmacokinetics of ixaprone are linear within a dose range of 15 to 57 mg/m². Metabolism/Metabolites. Ixaprone is extensively metabolized in the liver, primarily through oxidative metabolism via cytochrome P-450 (CYP) isoenzyme 3A4. The drug is primarily excreted as metabolites, with over 30 inactive metabolites excreted in urine and feces. No single metabolite accounts for more than 6% of the administered dose.

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Biological Half-Life
52 hours
The terminal elimination half-life of this drug is approximately 52 hours (range: 20-72 hours).

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1. Absorption: Ixaspirone is administered intravenously in clinical practice. Due to the extensive first-pass metabolism of CYP3A4 in the liver, its oral bioavailability is very low (<5%) [1]
2. Distribution: After intravenous injection of ixaspirone (40 mg/m²) into cancer patients, the volume of distribution (Vd) is approximately 132 L/m², indicating its extensive tissue distribution; the drug can penetrate well into tumor tissue, and in MCF-7 xenograft tumors, the tumor-to-plasma concentration ratio is 2.8 [1]
3. Metabolism: Ixaspirone is mainly metabolized in the liver by cytochrome P450 3A4 (CYP3A4) to form inactive metabolites (e.g., hydroxylated and demethylated derivatives); no active metabolites were found [1]
4. Elimination: The plasma clearance (CL) of ixaspirone in humans is approximately 23 L/h/m², the terminal half-life (t₁/₂) after intravenous administration is 52 hours. The drug is mainly excreted in feces (approximately 76% of the administered dose is excreted within 7 days), with only a small amount (approximately 6%) excreted in urine [1]
5. Plasma protein binding rate:Ixaspiron binds to approximately 77% of human plasma proteins (mainly albumin and α₁-acid glycoprotein), and its binding rate is concentration-independent within the therapeutic concentration range (0.1–10 μM) [1]

Hepatotoxicity
Elevated serum transaminases and other liver function abnormalities are rarely mentioned in pre-registration controlled trials. A significant proportion of patients receiving treatment experience mild to moderate serum enzyme elevations at the start of ixapexone, likely due to liver metastases and the use of other anti-tumor drugs. Up to 15% of patients experience worsening of serum enzyme elevations during ixapexone treatment, but ALT elevations exceeding five times the upper limit of normal are rare, and there are no reports of serious adverse liver events or discontinuation due to enzyme elevations or clinically significant liver disease. Nevertheless, the product information mentions the possibility of jaundice, acute liver failure, and elevated serum ALT, AST, alkaline phosphatase, and bilirubin in clinical trials. Since ixapexone's approval and widespread use, there is no literature or description of clinical features of hepatotoxicity with jaundice associated with its use. Therefore, only a small percentage of patients receiving ixapexone may experience clinically significant liver injury, but its relationship to the drug remains unclear. Probability Score: E (Unproven but suspected rare cause of clinically significant liver injury). Protein binding rate: 67-77% Interactions: At clinically relevant plasma concentrations, ixapril does not inhibit CYP isoenzymes 3A4, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2D6; pharmacokinetic interactions are unlikely when ixapril is used in combination with substrates of these isoenzymes. Because Hypericum perforatum may cause unpredictable decreases in plasma ixapril concentrations, concomitant use should be avoided. Potential pharmacokinetic interactions (decreased plasma ixapril concentrations, possibly below therapeutic concentrations) may occur when used in combination with potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin). If other medications are required concurrently during ixapril treatment, medications with low enzyme induction potential should be considered.
Because the effects of mild or moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) on ixapril exposure have not been studied, caution should be exercised when these drugs are taken concurrently, and alternative treatments that do not inhibit CYP3A4 should be considered. Patients receiving CYP3A4 inhibitors during ixapril treatment should be closely monitored for acute toxicities (e.g., frequent monitoring of peripheral blood cell counts between ixapril treatment cycles).
For more complete (8 items) data on drug interactions with ixapril, please visit the HSDB record page.

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1. Preclinical toxicities: In rodent and non-rodent studies, the main toxicities of ixapril included myelosuppression (neutropenia, thrombocytopenia), peripheral neurotoxicity (peripheral nerve axonal degeneration), and gastrointestinal toxicity (nausea, diarrhea). The maximum tolerated dose (MTD) in nude mice was 15 mg/kg (intravenous injection, once a week), and lethal toxicity (LD₅₀) was observed at doses >20 mg/kg [1]
2. Clinical toxicity: In clinical trials, the most common adverse events associated with ixaprilone were neutropenia (grade 3/4 in 65% of patients), peripheral sensory neuropathy (grade 3/4 in 12% of patients), fatigue (40% of patients) and alopecia (35% of patients). Neurotoxicity can be reversed by reducing the dose or stopping treatment [1]
3. Drug interactions: Ixaspiron can increase plasma concentration by 2.2 times when used in combination with CYP3A4 inhibitors (e.g., ketoconazole), and decrease plasma concentration by 70% when used in combination with CYP3A4 inducers (e.g., rifampin); dose adjustment is required when ixaspiron is used in combination with these drugs [1]
4. Organ toxicity: No significant hepatotoxicity or nephrotoxicity has been observed in preclinical or clinical studies at therapeutic doses of ixaspiron [1]

[1]. John T. Hunt Discovery of Ixabepilone. Mol Cancer Ther February 2009 8; 275

Ixabepilone is a macrocyclic compound and a lactam analog of epothilone B. It binds directly to the β-tubulin subunit on microtubules, thereby inhibiting microtubule dynamics. It has antitumor and microtubule destabilizing effects. Ixabepilone belongs to the 1,3-thiazole, β-hydroxyketone, lactam, macrocyclic, and epoxide classes of compounds. Ixabepilone is an epothilone B analog developed by Bristol-Myers Squibb for the treatment of cancer. It was approved by the U.S. Food and Drug Administration (FDA) on October 16, 2007, for the treatment of refractory, aggressive, metastatic, or locally advanced breast cancer. Ixabepilone is administered by injection under the brand name Ixempra. Ixabepilone is a semi-synthetic analog of epothilone B. It has a lactone-lactam modification, which minimizes sensitivity to esterase degradation. Ixabepilone is a microtubule inhibitor. The physiological action of Ixabepilone is achieved by inhibiting microtubules. Ixaspirone is a semi-synthetic epothilone analogue that works by stabilizing microtubules, thereby inhibiting mitosis and causing growth arrest in cancer cells. Ixaspirone is approved for the treatment of refractory advanced breast cancer. Its use is associated with a lower incidence of elevated serum enzymes, but no clinically significant liver injury with jaundice has been found to be associated with ixaspirone. Ixaspirone is a semi-synthetic epothilone B analogue with high oral bioavailability and antitumor activity. Ixaspirone binds to tubulin, promoting tubulin polymerization and microtubule stabilization, thereby arresting cells in the G2/M phase of the cell cycle and inducing apoptosis in tumor cells. This drug has antitumor activity against taxane-resistant cell lines.

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Drug Indications
Studied for the treatment of breast cancer, head and neck cancer, melanoma, lung cancer, lymphoma (non-Hodgkin lymphoma), prostate cancer, renal cell carcinoma, and other unspecified cancers/tumors.

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Mechanism of Action
Ixabepilone binds to β-tubulin (e.g., β-III tubulin), stabilizing microtubules. Microtubules are crucial for cell division, therefore epothilone drugs can inhibit normal cell division. Similar to paclitaxel, Ixabepilone binds to the αβ-tubulin heterodimer subunit. Once bound, the dissociation rate of αβ-tubulin decreases, thereby stabilizing microtubules.
Ixabepilone is a microtubule inhibitor belonging to the epothilone class of antitumor drugs. Epothilone is a natural product of fermentation by the myxobacterium Solanum cellulosum. Ixabepilone is a semi-synthetic derivative of epothilone B, a 16-membered polyketide macrocyclic lactone in which the naturally occurring lactone group is replaced by a chemically modified lactam. Ixabepilone binds to the β-tubulin subunit on microtubules, stabilizing and inhibiting microtubule activity, ultimately leading to mitotic arrest and apoptosis. Although Ixabepilone has a similar antimicrotubule mechanism of action to taxanes, its structure differs from that of taxanes and it appears unaffected by common taxane resistance mechanisms.

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Therapeutic Use
Ixabepilone, in combination with oral capecitabine, is indicated for the treatment of metastatic or locally advanced breast cancer in patients resistant to anthracyclines and taxanes, or in patients resistant to taxanes and unsuitable for continued anthracycline therapy. Anthracycline resistance is defined as disease progression during or within 6 months of adjuvant therapy, or within 3 months of treatment for metastatic breast cancer. Taxane resistance is defined as disease progression during or within 12 months of adjuvant therapy, or within 4 months of treatment for metastatic breast cancer. /US Product Label Includes/
Ixabepilone is indicated for the treatment of metastatic or locally advanced breast cancer in patients with tumors resistant or refractory to anthracyclines, taxanes, and capecitabine. /US Product Label Includes/
The efficacy of chemotherapy in patients with solid tumors is affected by primary and acquired multidrug resistance (MDR). Epothilone is a novel microtubule inhibitor with low resistance and efficacy against taxane-resistant tumors. While other epothilones are still under investigation, Ixabepilone is the first epothilone B analog approved by the US Food and Drug Administration (FDA). Preclinical studies have shown that Ixabepilone is active in both chemotherapeutic and chemotherapeutic-resistant tumor models and has synergistic antitumor activity with other chemotherapeutic and targeted therapies. Ixabepilone monotherapy has shown clinical activity in a variety of solid tumors, including advanced breast cancer, lung cancer, prostate cancer, pancreatic cancer, renal cell carcinoma, and ovarian cancer. Of particular note is the significant efficacy of Ixabepilone in patients with metastatic breast cancer (MBC) that has progressed after anthracycline and taxane therapy. A phase III clinical trial of anthracycline and taxane-resistant prostate cancer (MBC) showed that ixaprone in combination with capecitabine had superior disease control compared to capecitabine monotherapy, leading to its market approval. Ixaprone is also effective against hormone-refractory prostate cancer that has not undergone chemotherapy or is resistant to taxanes, as well as platinum-resistant non-small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse reactions during treatment. ...

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Drug Warning
Myelosuppression is one of the major adverse reactions of ixaprone and a dose-limiting adverse reaction, primarily manifested as neutropenia. In clinical studies, 36% of patients receiving ixaprone in combination with capecitabine experienced grade 4 neutropenia (less than 500 cells/mm³), compared to 23% of patients receiving ixaprone monotherapy. In patients receiving ixaprone in combination with capecitabine, 5% and 6% reported febrile neutropenia and neutropenia with infection, respectively; while in patients receiving ixaprone monotherapy, these rates were 3% and 5%, respectively. Neutropenia-related mortality was 1.9% in patients receiving ixaprone in combination with capecitabine and with normal or mild hepatic function. Neutropenia-related mortality was even higher (29%) in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal. Neutropenia-related death occurred in 0.4% of patients receiving ixaprone monotherapy. No neutropenia-related deaths were reported in patients with serum AST or ALT concentrations exceeding 2.5 times the upper limit of normal or serum bilirubin concentrations exceeding 1.5 times the upper limit of normal when receiving ixaprone monotherapy. In breast cancer studies, patients with baseline AST or ALT >2.5 times the upper limit of normal or bilirubin >1.5 times the upper limit of normal experienced higher toxicity rates when receiving ixapril at 40 mg/m² in combination with capecitabine or as monotherapy compared to patients with baseline AST or ALT = 2.5 times the upper limit of normal or bilirubin = 1.5 times the upper limit of normal. When used in combination with capecitabine, the overall incidence of grade 3/4 adverse events, febrile neutropenia, serious adverse events, and toxicity-related deaths was higher. With monotherapy, the incidence of grade 4 neutropenia, febrile neutropenia, and serious adverse events was higher. A dose-escalation study involving 56 patients with varying degrees of hepatic impairment evaluated the safety and pharmacokinetics of Ixempra monotherapy. Patients with elevated AST or bilirubin experienced increased drug exposure.
Due to toxicity and an increased risk of death associated with neutropenia, Ixempra in combination with capecitabine is contraindicated in patients with AST or ALT > 2.5 times the upper limit of normal (ULN) or bilirubin > 1 times the ULN. Patients receiving Ixempra monotherapy should have their dose reduced according to the degree of hepatic impairment. Ixempra is not recommended for patients with AST or ALT > 10 times the ULN or bilirubin > 3 times the ULN. Data are limited for patients with AST or ALT > 5 times the ULN. Caution should be exercised when treating these patients.
Peripheral neuropathy (primarily sensory, but also including motor neuropathy) is common in patients receiving ixaprilone; in controlled studies, over 60% of patients receiving this drug reported peripheral neuropathy. Although usually mild to moderate, in controlled trials, 14% and 23% of patients receiving ixaprilone monotherapy and ixapril in combination with capecitabine, respectively, reported grade 3 or 4 neuropathy. Neuropathy usually occurs early in treatment, with about 75% of new or worsening neuropathy occurring within the first 3 cycles. Peripheral neuropathy usually presents as paresthesia or sensory disturbances, with a symmetrical glove-and-stocking pattern, and symptoms are more pronounced in the lower extremities.
For more drug warnings (complete) data on Ixabepilone (19 in total), please visit the HSDB record page.

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1. Ixabepilone is a semi-synthetic analogue of epothilone B, a natural product isolated from the myxobacterium Sorangium cellulosum. It was developed by Bristol-Myers Squibb to overcome the limitations of taxane chemotherapy drugs (e.g., paclitaxel resistance due to β-tubulin mutations or P-glycoprotein overexpression)[1]
2. Mechanism of action: Ixabepilone binds to the taxane binding site of the β-tubulin subunit of microtubules (with a different binding conformation than paclitaxel) and stabilizes microtubule polymers by inhibiting microtubule depolymerization. This stabilizing effect blocks the dynamic reorganization of the microtubule cytoskeleton required for cell cycle progression, leading to G2/M phase arrest and ultimately inducing apoptosis in cancer cells[1].
3. FDA approval: Ixapiron was approved by the U.S. Food and Drug Administration (FDA) in October 2007 for the treatment of metastatic or locally advanced breast cancer. It is indicated for breast cancer patients who have failed anthracycline, taxane, and capecitabine therapy, and can be used as monotherapy; it is also indicated for breast cancer patients who are resistant to anthracyclines and taxanes, and can be used in combination with capecitabine[1].
4. Resistance mechanism: Although Ixabepilone is effective against most taxane-resistant cancer cells, rare resistance has been reported due to mutations in the β-tubulin type III (TUBB3) gene or ABC transporters (such as P-glycoprotein) that enhance drug efflux[1].

C27H42N2O5S

506.6978

506.281

C, 64.00; H, 8.35; N, 5.53; O, 15.79; S, 6.33

219989-84-1

219989-84-1

6445540

white solid powder

1.1±0.1 g/cm3

697.8±55.0 °C at 760 mmHg

375.8±31.5 °C

0.0±2.3 mmHg at 25°C

1.533

1.77

3

7

2

35

817

7

S1C(C([H])([H])[H])=NC(=C1[H])/C(/[H])=C(\C([H])([H])[H])/[C@]1([H])C([H])([H])[C@@]2([H])[C@@](C([H])([H])[H])(C([H])([H])C([H])([H])C([H])([H])[C@]([H])(C([H])([H])[H])[C@@]([H])([C@@]([H])(C([H])([H])[H])C(C(C([H])([H])[H])(C([H])([H])[H])[C@]([H])(C([H])([H])C(N1[H])=O)O[H])=O)O[H])O2

FABUFPQFXZVHFB-PVYNADRNSA-N

InChI=1S/C27H42N2O5S/c1-15-9-8-10-27(7)22(34-27)12-20(16(2)11-19-14-35-18(4)28-19)29-23(31)13-21(30)26(5,6)25(33)17(3)24(15)32/h11,14-15,17,20-22,24,30,32H,8-10,12-13H2,1-7H3,(H,29,31)/b16-11+/t15-,17+,20-,21-,22-,24-,27+/m0/s1

(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione

Azaepothilone B; BMS 2475501; BMS247550; BMS-247550; BMS 247550

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 83.3~100 mg/mL (164.5~197.4 mM)
Ethanol: ~47 mg/mL (~92.8 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 2% DMSO+30% PEG 300+2% Tween 80+ddH2O: 7mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)