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| Targets |
The primary target of Cemadotin is tubulin, through which it exerts its antitumor activity by binding to tubulin and suppressing microtubule dynamics. Scatchard analysis reveals two affinity classes of cemadotin-binding sites on tubulin with Kd values of 19.4 μM and 136 μM. The compound binds at a site distinct from that of vinblastine, as vinblastine does not inhibit cemadotin binding to tubulin and vice versa, suggesting a novel binding site on tubulin. Cemadotin exhibits an inhibition constant Ki of approximately 1 μM for tubulin.
Cemadotin targets tubulin, a key component of the microtubule cytoskeleton. By binding to tubulin at the vinca-binding site, cemadotin inhibits tubulin polymerization and prevents the formation of mitotic spindles. This disruption of microtubule dynamics leads to cell cycle arrest in the G2/M phase, which is a critical checkpoint in cell division. Cells arrested in mitosis eventually undergo apoptosis, leading to the elimination of rapidly dividing cancer cells. |
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| ln Vitro |
Cemadotin (0-100 μM; 35 min) inhibits polymerization in Strongylocentrotus purpuratus treated with tubulin in a dose-dependent manner [1]. The pace and extent of tubulin excursion growth are preferentially inhibited by cemadotin (0-1000 nM), and the inhibitory effect is depending on drug concentration [1]. Simadotin (0–1 μM) greatly boosts the frequency of rescues but has minimal impact on the frequency of disasters [1]. HEK 293, F9, and HL60 cancer cells are inhibited by cemadotin (400 pM~300 nM; 72 h)[2].
Cemadotin demonstrates extremely potent antiproliferative activity in vitro. Against various tumor cell lines, the compound exhibits IC₅₀ values as low as 0.1 nM, indicating nanomolar-level cytotoxicity. In tubulin polymerization inhibition assays, Cemadotin inhibits microtubule polymerization in a concentration-dependent manner with an IC₅₀ of 7 μM and induces depolymerization of preassembled microtubules. Quantitative video microscopy of individual microtubules reveals that Cemadotin strongly suppresses dynamic instability: it reduces the rate and extent of growing and shortening, increases rescue frequency, and increases the percentage of time microtubules spend in an attenuated or paused state. At the lowest effective concentrations, dynamics are suppressed without significant microtubule depolymerization. Cell cycle analysis indicates that Cemadotin treatment blocks tumor cells in the G2-M phase. Cemadotin exhibits potent in vitro cytotoxic activity against a wide range of human cancer cell lines, including those derived from breast, lung, colon, and ovarian cancers. The compound has IC50 values in the nanomolar to sub-nanomolar range. It effectively induces G2/M cell cycle arrest and apoptosis in cancer cells. Cemadotin has also been shown to inhibit the migration and invasion of cancer cells, suggesting potential anti-metastatic activity. |
| ln Vivo |
Cemadotin demonstrates significant antitumor activity in animal models. Studies show that this compound inhibits the growth of human tumor xenografts. In nude mouse models, Cemadotin exerts its antimitotic effects by suppressing spindle microtubule dynamics, thereby preventing tumor cell proliferation. However, in human clinical trials, Cemadotin as a single agent failed to induce objective tumor responses, with only minor tumor regressions observed. This finding suggests that the in vivo antitumor activity of this compound may be limited by its pharmacokinetic properties or toxicity profile.
In vivo, cemadotin has demonstrated antitumor activity in various preclinical models of cancer. The compound has been evaluated in murine xenograft models of human solid tumors, where it showed significant tumor growth inhibition. Based on its promising preclinical activity, cemadotin was advanced to clinical trials for the treatment of advanced solid tumors. However, clinical development was limited by toxicity and lack of sufficient efficacy in some patient populations. |
| Enzyme Assay |
The binding affinity of Cemadotin to tubulin can be assessed using equilibrium dialysis or Scatchard analysis. Purified bovine brain tubulin (devoid of microtubule-associated proteins) is incubated with various concentrations of ³H-labeled cemadotin in tubulin binding buffer at 37°C. Bound and free ligands are separated by centrifugation or filtration, and radioactivity is measured using a liquid scintillation counter. Non-specific binding is defined using excess unlabeled cemadotin (e.g., 100-fold molar excess). Binding data are analyzed by Scatchard plot to calculate Kd values and binding site numbers. Tubulin polymerization inhibition assays employ turbidimetry: the increase in absorbance at 340 nm or 350 nm is monitored at 37°C in GTP-containing polymerization buffer to calculate the polymerization inhibition rate.
Cemadotin's activity can be assessed using in vitro tubulin polymerization assays. These assays measure the compound's ability to inhibit the polymerization of purified tubulin into microtubules, typically using turbidimetric methods. The compound's binding affinity to tubulin can be evaluated using competitive binding assays with radiolabeled vinblastine or other vinca-site binders. Fluorescence-based assays can also be used to monitor tubulin polymerization. |
| Cell Assay |
Cell proliferation assay[2]
Cell Types: HEK 293, F9 and HL60 Tested Concentrations: 400 pM~300 nM Incubation Duration: 72 h Experimental Results: demonstrated cytotoxicity to HEK 293, F9 and HL60, with IC50 of 0.7 nM, 14.8 nM and HL60 respectively. 0.5 nM, respectively. Exponentially growing tumor cells (e.g., human leukemia cells or solid tumor cell lines) are seeded into 96-well culture plates at densities of 5,000-10,000 cells/well in medium containing 10% fetal bovine serum and cultured overnight. The following day, various concentrations of Cemadotin (e.g., 0.001-100 nM) are added and incubated for 48-96 hours. Cell viability is assessed using MTT or CellTiter-Glo luminescent assays, with absorbance measured at 570 nm or corresponding wavelengths using a microplate reader. For cell cycle analysis, cells are fixed with 70% ethanol after Cemadotin treatment for 24 hours, stained with propidium iodide, and analyzed by flow cytometry. Tubulin polymerization status can be observed by immunofluorescence microscopy using anti-α-tubulin antibodies. Cellular assays for cemadotin typically involve treating cancer cell lines with the compound and measuring cell viability, proliferation, and cell cycle distribution. MTT or CellTiter-Glo assays are commonly used to assess cytotoxicity. Flow cytometry with propidium iodide staining is used to evaluate cell cycle arrest in the G2/M phase. Apoptosis can be assessed using annexin V staining, caspase activation assays, or PARP cleavage detection by Western blotting. |
| Animal Protocol |
Six-to-eight-week-old female nude mice are subcutaneously inoculated with human tumor cells (e.g., breast cancer, lung cancer, or colon cancer cell lines, 5×10⁶ cells/100 μL PBS). When tumor volumes reach approximately 100-150 mm³, animals are randomly assigned to treatment groups (6-10 mice per group). Cemadotin is prepared in saline and administered via tail vein injection or intraperitoneal injection using various dosing schedules including daily, weekly, or every-three-week regimens, with doses ranging from 1-20 mg/kg. Tumor volume (length × width²/2) and body weight are measured 2-3 times per week. At the end of the experiment (typically 21-28 days or when tumor volume reaches 2000 mm³), animals are euthanized, tumor inhibition rates are calculated, and tumor tissues are collected for histopathological analysis and immunohistochemical detection (e.g., Ki-67 proliferation index, TUNEL apoptosis assay).
In vivo animal model protocols for cemadotin involve its administration (typically intravenously) to tumor-bearing mice. Xenograft models using human cancer cell lines are commonly used. Tumor growth is monitored by caliper measurements, and tumor weight is determined at the end of the study. Pharmacokinetic studies are also performed to determine the compound's half-life, clearance, and tissue distribution. Toxicology studies are conducted to evaluate the compound's safety profile. |
| ADME/Pharmacokinetics |
The pharmacokinetics of Cemadotin in humans have been evaluated in Phase I clinical trials. Following intravenous bolus administration (5 minutes), the plasma concentration-time profile of Cemadotin fits a two-compartment model. At the 20 mg/m² dose level, the key pharmacokinetic parameters are: maximum concentration (Cmax) 9.0 ± 7.2 μM, area under the curve (AUC) 37.3 ± 6.8 μM·h, plasma clearance 0.8 ± 0.14 L/h/m², volume of distribution at steady state 9.6 ± 2.0 L/m², and terminal elimination half-life 10.3 ± 1.5 h. The AUC increases from 4.6 μM·h at the 2.5 mg/m² dose level to 37.3 μM·h at 20 mg/m², suggesting linear pharmacokinetics within the tested dose range. With 24-hour continuous infusion, the terminal half-life is approximately 10 hours, the steady-state volume of distribution is approximately 9 L/m², and total clearance is approximately 0.6 L/h/m².
Cemadotin is administered intravenously. Pharmacokinetic data from clinical trials indicate that the compound has a short half-life and is rapidly cleared from the circulation. The compound is extensively metabolized, and its metabolites are excreted primarily in the urine. Dose-limiting toxicities observed in clinical trials included myelosuppression and neurotoxicity. The compound's pharmacokinetic profile is characterized by high inter-patient variability. |
| Toxicity/Toxicokinetics |
The dose-limiting toxicity of Cemadotin is cardiovascular toxicity, primarily manifested as reversible hypertension and cardiac ischemic events. In Phase I trials with intravenous bolus administration, dose-limiting toxicity was reached at 20 mg/m², including reversible hypertension and myocardial infarction. In 24-hour continuous infusion trials, hypertension was observed at all dose levels, but grade 3 hypertension only occurred at dose levels of 20.0, 25.0, and 27.5 mg/m², with some patients exhibiting signs of cardiac ischemia. Other common toxicities include nausea, vomiting, drug fever, tumor site pain, asthenia, as well as neutropenia and transient liver enzyme elevation. Notably, Cemadotin does not cause significant myelosuppression. This compound is intended for scientific research use only and is not for human therapeutic applications.
The toxicity profile of cemadotin is characterized primarily by myelosuppression (neutropenia, thrombocytopenia) and neurotoxicity (peripheral neuropathy). These toxicities are typical of antimitotic agents and are dose-limiting. Other adverse effects may include gastrointestinal disturbances, fatigue, and alopecia. The compound's toxicity profile was a major factor limiting its clinical development. |
| References | |
| Additional Infomation |
Cemadotin (CAS# 159776-69-9) is a synthetic analogue of the marine natural product dolastatin 15. It is a potent antimitotic agent that inhibits tubulin polymerization and disrupts microtubule dynamics. Cemadotin was developed as a potential anticancer agent and evaluated in clinical trials for various solid tumors. It binds to tubulin at the vinca-binding site, leading to G2/M cell cycle arrest and apoptosis. Clinical development was limited by myelosuppression and neurotoxicity.
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| Molecular Formula |
C35H56N6O5
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|---|---|
| Molecular Weight |
640.86
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| Exact Mass |
640.431
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| Elemental Analysis |
C, 65.60; H, 8.81; N, 13.11; O, 12.48
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| CAS # |
159776-69-9
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| Related CAS # |
159776-69-9;172837-41-1 (HCl);
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| PubChem CID |
178028
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| Sequence |
N(Me2)Val-Val-N(Me)Val-Pro-Pro-NHBn; N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline benzylamide
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| SequenceShortening |
VVVPP
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.138g/cm3
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| Boiling Point |
857.7ºC at 760mmHg
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| Flash Point |
472.5ºC
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| Vapour Pressure |
0mmHg at 25°C
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| Index of Refraction |
1.545
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| LogP |
3.152
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
46
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| Complexity |
1070
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| Defined Atom Stereocenter Count |
5
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| SMILES |
CC([C@H](NC([C@@H](N(C)C)C(C)C)=O)C(N([C@H](C(N1CCC[C@H]1C(N2CCC[C@H]2C(NCC3=CC=CC=C3)=O)=O)=O)C(C)C)C)=O)C
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| InChi Key |
LSIZJZZMXCWHBR-IIZANFQQSA-N
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| InChi Code |
InChI=1S/C35H56N6O5/c1-22(2)28(36-7)34(45)40-20-14-18-27(40)33(44)41(32(43)26-17-13-19-39(26)21-25-15-11-10-12-16-25)35(46)29(23(3)4)37-31(42)30(24(5)6)38(8)9/h10-12,15-16,22-24,26-30,36H,13-14,17-21H2,1-9H3,(H,37,42)/t26-,27-,28-,29-,30-/m0/s1
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| Chemical Name |
(2S)-1-benzyl-N-[(2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-N-[(2S)-1-[(2S)-3-methyl-2-(methylamino)butanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide
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| Synonyms |
LU103793; LU-103793; Cemadotin; 159776-69-9; cemadotina; cemadotine; 6SQ8M7ZSFV; LU 103793
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5604 mL | 7.8020 mL | 15.6040 mL | |
| 5 mM | 0.3121 mL | 1.5604 mL | 3.1208 mL | |
| 10 mM | 0.1560 mL | 0.7802 mL | 1.5604 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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