Cabazitaxel
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MedKoo CAT#: 200585

CAS#: 183133-96-2

Description: Cabazitaxel is a semi-synthetic derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB).


Chemical Structure

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Cabazitaxel
CAS# 183133-96-2

Theoretical Analysis

MedKoo Cat#: 200585
Name: Cabazitaxel
CAS#: 183133-96-2
Chemical Formula: C45H57NO14
Exact Mass: 835.37791
Molecular Weight: 835.93
Elemental Analysis: C, 64.66; H, 6.87; N, 1.68; O, 26.80.

Price and Availability

Size Price Availability Quantity
100.0mg USD 150.0 Same day
500.0mg USD 450.0 Same day
1.0g USD 850.0 Same day
2.0g USD 1450.0 Same day
5.0g USD 2950.0 Same day
10.0g USD 4250.0 2 Weeks
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Related CAS #: 183133-96-2   1383561-29-2 (d6-labeled)   1383572-18-6 (d3-labeled)   1383572-17-5 (d3-labeled)    

Synonym: XRP6258; XRP-6258; XRP 6258; TXD 258; TXD-258; TXD258; RPR116258A; axoid XRP6258; dimethoxydocetaxel US brand name: Jevtana.

IUPAC/Chemical Name: (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-9-(((2R,3S)-3-((tert-butoxycarbonyl)amino)-2-hydroxy-3-phenylpropanoyl)oxy)-11-hydroxy-4,6-dimethoxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-12-yl benzoate.

InChi Key: BMQGVNUXMIRLCK-OAGWZNDDSA-N

InChi Code: InChI=1S/C45H57NO14/c1-24-28(57-39(51)33(48)32(26-17-13-11-14-18-26)46-40(52)60-41(3,4)5)22-45(53)37(58-38(50)27-19-15-12-16-20-27)35-43(8,36(49)34(55-10)31(24)42(45,6)7)29(54-9)21-30-44(35,23-56-30)59-25(2)47/h11-20,28-30,32-35,37,48,53H,21-23H2,1-10H3,(H,46,52)/t28-,29-,30+,32-,33+,34+,35-,37-,43+,44-,45+/m0/s1

SMILES Code: O=C(O[C@@H]([C@@]1([H])[C@@]2(C)[C@@H](OC)C[C@@]3([H])OC[C@]31OC(C)=O)[C@]4(O)C[C@H](OC([C@H](O)[C@@H](NC(OC(C)(C)C)=O)C5=CC=CC=C5)=O)C(C)=C(C4(C)C)[C@@H](OC)C2=O)C6=CC=CC=C6

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Cabazitaxel (RPR-116258A, XRP6258, TXD 258, Taxoid XRP6258) is a semi-synthetic derivative of a natural taxoid that kills cancer cells by inhibiting cell division and growth.
In vitro activity: Cabazitaxel had similar efficiency compared with docetaxel for reducing the lag time for tubulin assembly (LT50 = 0–0.1 μmol/L for both) and the rate of cold-induced microtubule depolymerization (dIC50 = 0.1–0.25 μmol/L for both) in vitro (Table 2). In vitro antiproliferative activity in chemotherapy-sensitive and -resistant cell lines. Cabazitaxel showed similar antiproliferative activity compared with docetaxel in cell lines sensitive to chemotherapy (murine leukemia P388, human tumor HL60 and KB, and breast Calc18), as shown by the similar IC50 ranges across different cell types (cabazitaxel, 0.004–0.041 μmol/L; docetaxel, 0.008–0.079 μmol/L; Table 3). In P-glycoprotein–expressing cell lines with in vitro–acquired resistance to taxanes (P388/TXT, Calc18/TXT, and HL60/TAX) or to other chemotherapy agents (P388/DOX, P388/VCR, and KBV1), cabazitaxel was found to be more active than docetaxel (IC50 ranges: cabazitaxel, 0.013–0.414 μmol/L; docetaxel, 0.17–4.01 μmol/L). Resistance factors (an indication of the difference in drug concentrations needed to inhibit resistant vs. sensitive/parental cell lines) were 2 to 10 for cabazitaxel and 5 to 59 for docetaxel. Cell lines expressing moderate levels of P-glycoprotein (P388/TXT, P388/VCR, HL60/TAX, and Calc18/TXT), which may be more clinically representative, had minimal cross-resistance to cabazitaxel (resistance factors = 2–4). Reference: Clin Cancer Res. 2013 Jun 1;19(11):2973-83. https://clincancerres.aacrjournals.org/content/19/11/2973.long
In vivo activity: The pharmacokinetic profile of cabazitaxel was evaluated in mice bearing docetaxel-sensitive murine mammary MA16/C adenocarcinoma tumors. Cabazitaxel was highly active in this tumor model, inducing CRs in 80% of mice and having a log cell kill of 3.7 at the HNTD of 40 mg/kg (Table 1). This antitumor activity was consistent with drug uptake into the tumor, which was both rapid (maximum drug concentrations were reached 15 minutes after dosing) and sustained (at 48 hours post-dose, cabazitaxel concentrations were 40-fold higher in the tumor vs. plasma; Fig. 1). Ratios of cabazitaxel exposure in tumors versus plasma were 1.6 from 0 to 48 hours and 2.9 over the entire experimental period. Cabazitaxel concentrations were maintained above the range of cellular antiproliferative IC50 values [0.004–0.041 μmol/L (see Table 3), corresponding to 3–29 ng/mL, 4-day exposure] for 24 hours in plasma and 96 hours in the tumor. Reference: Clin Cancer Res. 2013 Jun 1;19(11):2973-83. https://clincancerres.aacrjournals.org/content/19/11/2973.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 119.63

Preparing Stock Solutions

The following data is based on the product molecular weight 835.93 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Vrignaud P, Sémiond D, Lejeune P, Bouchard H, Calvet L, Combeau C, Riou JF, Commerçon A, Lavelle F, Bissery MC. Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 2013 Jun 1;19(11):2973-83. doi: 10.1158/1078-0432.CCR-12-3146. Epub 2013 Apr 15. PMID: 23589177. 2. Azarenko O, Smiyun G, Mah J, Wilson L, Jordan MA. Antiproliferative mechanism of action of the novel taxane cabazitaxel as compared with the parent compound docetaxel in MCF7 breast cancer cells. Mol Cancer Ther. 2014 Aug;13(8):2092-103. doi: 10.1158/1535-7163.MCT-14-0265. Epub 2014 Jun 30. PMID: 24980947.
In vitro protocol: 1. Vrignaud P, Sémiond D, Lejeune P, Bouchard H, Calvet L, Combeau C, Riou JF, Commerçon A, Lavelle F, Bissery MC. Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 2013 Jun 1;19(11):2973-83. doi: 10.1158/1078-0432.CCR-12-3146. Epub 2013 Apr 15. PMID: 23589177. 2. Azarenko O, Smiyun G, Mah J, Wilson L, Jordan MA. Antiproliferative mechanism of action of the novel taxane cabazitaxel as compared with the parent compound docetaxel in MCF7 breast cancer cells. Mol Cancer Ther. 2014 Aug;13(8):2092-103. doi: 10.1158/1535-7163.MCT-14-0265. Epub 2014 Jun 30. PMID: 24980947.
In vivo protocol: 1. Vrignaud P, Sémiond D, Lejeune P, Bouchard H, Calvet L, Combeau C, Riou JF, Commerçon A, Lavelle F, Bissery MC. Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 2013 Jun 1;19(11):2973-83. doi: 10.1158/1078-0432.CCR-12-3146. Epub 2013 Apr 15. PMID: 23589177.

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1: Abidi A. Cabazitaxel: A novel taxane for metastatic castration-resistant prostate cancer-current implications and future prospects. J Pharmacol Pharmacother. 2013 Oct;4(4):230-237. Review. PubMed PMID: 24250198; PubMed Central PMCID: PMC3825997.

2: Kearns B, Lloyd Jones M, Stevenson M, Littlewood C. Cabazitaxel for the second-line treatment of metastatic hormone-refractory prostate cancer: a NICE single technology appraisal. Pharmacoeconomics. 2013 Jun;31(6):479-88. doi: 10.1007/s40273-013-0050-9. Review. PubMed PMID: 23580356.

3: Keating GM. Cabazitaxel: a guide to its use in hormone-refractory metastatic prostate cancer. Drugs Aging. 2013 May;30(5):359-65. doi: 10.1007/s40266-013-0078-8. Review. PubMed PMID: 23532557.

4: Cheetham P, Petrylak DP. Tubulin-targeted agents including docetaxel and cabazitaxel. Cancer J. 2013 Jan-Feb;19(1):59-65. doi: 10.1097/PPO.0b013e3182828d38. Review. PubMed PMID: 23337758.

5: Yap TA, Pezaro CJ, de Bono JS. Cabazitaxel in metastatic castration-resistant prostate cancer. Expert Rev Anticancer Ther. 2012 Sep;12(9):1129-36. doi: 10.1586/era.12.88. Review. PubMed PMID: 23098113.

6: Malhotra M, Dhingra R, Sharma T, Deep A, Narasimhan B, Phogat P, Sharma PC. Cabazitaxel: a novel drug for hormone-refractory prostate cancer. Mini Rev Med Chem. 2013 May 1;13(6):915-20. Review. PubMed PMID: 22950608.

7: Doyle-Lindrud S. Managing side effects of the novel taxane cabazitaxel in castrate-resistant prostate cancer. Clin J Oncol Nurs. 2012 Jun 1;16(3):286-91. doi: 10.1188/12.CJON.286-291. Review. PubMed PMID: 22641321.

8: Pean E, Demolis P, Moreau A, Hemmings RJ, O'Connor D, Brown D, Shepard T, Abadie E, Pignatti F. The European Medicines Agency review of cabazitaxel (Jevtana®) for the treatment of hormone-refractory metastatic prostate cancer: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2012;17(4):543-9. doi: 10.1634/theoncologist.2011-0364. Epub 2012 Apr 3. Review. PubMed PMID: 22477727; PubMed Central PMCID: PMC3336839.

9: Villanueva C, Bazan F, Kim S, Demarchi M, Chaigneau L, Thiery-Vuillemin A, Nguyen T, Cals L, Dobi E, Pivot X. Cabazitaxel: a novel microtubule inhibitor. Drugs. 2011 Jul 9;71(10):1251-8. doi: 10.2165/11591390-000000000-00000. Review. Erratum in: Drugs. 2011 Sep 10;71(13):1720. PubMed PMID: 21770474.

10: Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2011 Mar 10;5:117-24. doi: 10.2147/DDDT.S13029. Review. Erratum in: Drug Des Devel Ther. 2011;5:183. PubMed PMID: 21448449; PubMed Central PMCID: PMC3063116.



Additional Information

Chemical structure of cabazitaxel
Comparing to the chemical structure of docetaxel, cabazitaxel has two more methyl groups. For this reason, cabazitaxel is also called dimethoxydocetaxel (see the following chemical structures).
 
Scheme 1: chemical structures of cabazitaxel and docetaxel
 
Cabazitaxel: Drug Description
JEVTANA (cabazitaxel) is an antineoplastic agent belonging to the taxane class. It is prepared by semi-synthesis with a precursor extracted from yew needles. The chemical name of cabazitaxel is (2α,5β;,7β;,10β;,13α)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9oxo-5,20-epoxytax-11-en-2-yl benzoate – propan-2-one(1:1). Cabazitaxel is a white to off-white powder with a molecular formula of C45H57NO14•C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol.  JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 g polysorbate 80. Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80. DILUENT for JEVTANA is a clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.  JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.
 
Cabazitaxel: Mechanism of Action
The taxanes act by binding to microtubules, cytoskeletal polymers composed of α-tubulin and β-tubulin heterodimers. The binding of taxanes to tubulin promotes the stabilization of GDP-bound tubulin in the microtubule resulting in inhibition of disassembly and prevention of subsequent mitosis and cell division.  Derived from the bark of yew trees, in 1992, paclitaxel was the first taxane approved by the Food and Drug Administration (FDA) as an anti-neoplastic agent. Docetaxel, a semisynthetic analog with increased potency, was approved by the FDA in 1996 for the treatment advanced breast cancer and later in 2004 for the treatment of metastatic CRPC. These earlier generation taxanes have high substrate affinity for the ATP-dependent drug efflux pump P-glycoprotein 1 (P-gp1). Therefore, P-gp1 is thought to account for, at least in part, both inherent and acquired resistance to these agents.
 
Cabazitaxel, also known as XRP6258, is a semi-synthetic taxane from a single diastereoisomer of 10-deacetyl baccatin III, and derived from the needles of various Taxus species. By binding to tubulin, cabazitaxel inhibits microtubule depolymerization and cell division, resulting in cell cycle arrest. This compound was selected for clinical testing due to its poor affinity for ATP-dependent drug efflux pump P-gp1, and its greater blood-brain barrier penetration compared to paclitaxel and docetaxel. Cabazitaxel has also demonstrated superior in vitro cytotoxicity compared to docetaxel in several murine and human cancer cell lines. ( source: Clinical Development of Cabazitaxel for the Treatment of Castration-Resistant Prostate Cancer . Che-Kai Tsao, Sonia Seng, William K. Oh, and Matthew D. Galsky Division of Hematology and Medical Oncology, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117627/ ).