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| Name | Cabazitaxel | ||||||||||||||||||||||||||||||||||||||||||
| Accession Number | DB06772 | ||||||||||||||||||||||||||||||||||||||||||
| Type | small molecule | ||||||||||||||||||||||||||||||||||||||||||
| Groups | approved | ||||||||||||||||||||||||||||||||||||||||||
| Description | Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010. |
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| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
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| Synonyms |
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| Salts | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| Brand mixtures | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| CAS number | 183133-96-2 | ||||||||||||||||||||||||||||||||||||||||||
| Weight |
Average: 835.9324 Monoisotopic: 835.377905537 |
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| Chemical Formula | C45H57NO14 | ||||||||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=BMQGVNUXMIRLCK-OAGWZNDDSA-N | ||||||||||||||||||||||||||||||||||||||||||
| InChI |
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
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| IUPAC Name |
(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0^{3,10}.0^{4,7}]heptadec-13-en-2-yl benzoate
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| SMILES |
[H][C@@](O)([C@@H](NC(=O)OC(C)(C)C)C1=CC=CC=C1)C(=O)O[C@@]1([H])C[C@@]2(O)[C@@]([H])(OC(=O)C3=CC=CC=C3)[C@]3([H])[C@@]4(CO[C@]4([H])C[C@]([H])(OC)[C@@]3(C)C(=O)[C@]([H])(OC)C(=C1C)C2(C)C)OC(C)=O
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| Mass Spec | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Taxonomy | |||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | ||||||||||||||||||||||||||||||||||||||||||
| Classes | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Substructures |
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| Pharmacology | |||||||||||||||||||||||||||||||||||||||||||
| Indication | For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen. | ||||||||||||||||||||||||||||||||||||||||||
| Pharmacodynamics | Cabaitaxel has anti-tumour properties and is effective against docetaxel-sensitive and -insensitive tumours. | ||||||||||||||||||||||||||||||||||||||||||
| Mechanism of action | Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the interference of mitotic and interphase cellular functions. The cell is then unable to progress further into the cell cycle, being stalled at metaphase, thus triggering apoptosis of the cancer cell. | ||||||||||||||||||||||||||||||||||||||||||
| Absorption | After an intravenous dose of cabazitaxel 25 mg/m2 every three weeks to a population of 170 patients with solid tumors, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng.h/mL (CV 34%). Administration with prednisone or prednisolone do not effect the pharmacokinetic profile of cabazitaxel. | ||||||||||||||||||||||||||||||||||||||||||
| Volume of distribution | The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a median BSA of 1.84 m2) at steady state. Compared to other taxanes, penetrates the CNS to a greater extent. |
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| Protein binding | Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). | ||||||||||||||||||||||||||||||||||||||||||
| Metabolism | Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8 which results in 20 different metabolites. Two of these metabolites are active demethylated derivatives of cabaxitaxel and referred to as RPR112698 and RPR123142 respectively. Docetaxel is another metabolite of cabazitaxel. Cabazitaxel is the main circulating moiety in human plasma. | ||||||||||||||||||||||||||||||||||||||||||
| Route of elimination | After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). | ||||||||||||||||||||||||||||||||||||||||||
| Half life | Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively. | ||||||||||||||||||||||||||||||||||||||||||
| Clearance | Cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer. |
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| Toxicity | Cabazitaxel may cause serious side effects including neutropenia, hypersensitivity reactions, gastrointestinal symptoms, and renal failure. Anticipated complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Cabazitaxel penetrates the blood-brain barrier. LD50, rat = 500 mg/kg | ||||||||||||||||||||||||||||||||||||||||||
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| Pathways | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| Manufacturers | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Packagers | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| Properties | |||||||||||||||||||||||||||||||||||||||||||
| State | solid | ||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Predicted Properties |
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| Synthesis Reference | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| General Reference |
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| PDB Entries | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| FDA label | show (383 KB) | ||||||||||||||||||||||||||||||||||||||||||
| MSDS | show (99.2 KB) | ||||||||||||||||||||||||||||||||||||||||||
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| Drug Interactions |
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| Food Interactions | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Targets |
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Pharmacological action: yes
Actions: binder Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha-chain Organism class: humanUniProt ID: P68366  Gene: TUBA4A Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
Pharmacological action: yes
Actions: binder Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha-chain Organism class: humanUniProt ID: Q9H4B7 Gene: TUBB1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
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| Enzymes |
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Actions: substrate
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide UniProt ID: P08684Gene: CYP3A4 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
Actions: substrate
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics UniProt ID: P20815Gene: CYP3A5 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
Actions: substrate
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol) UniProt ID: P10632Gene: CYP2C8 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
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| Transporters |
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1. Multidrug resistance protein 1 Actions: substrate, inhibitorEnergy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells UniProt ID: P08183Gene: ABCB1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
2. ATP-binding cassette sub-family G member 2 Actions: inhibitorXenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123 UniProt ID: Q9UNQ0Gene: ABCG2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
3. Solute carrier organic anion transporter family member 1B1 Actions: inhibitorMediates the Na(+)-independent transport of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. May play an important role in the clearance of bile acids and organic anions from the liver UniProt ID: Q9Y6L6Gene: SLCO1B1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
4. Solute carrier organic anion transporter family member 1B3 Actions: inhibitorMediates the Na(+)-independent transport of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotrexate and sulfobromophthalein (BSP) UniProt ID: Q9NPD5Gene: SLCO1B3 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References:
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