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Purity: ≥98%
Dolastatin 10 (also known as DLS 10), a peptide-based natural product isolated from the marine mollusk Dolabela auricularia, is a highly potent antimitotic peptide that inhibits tubulin polymerization with an IC50 value of 1.2μM. It is an analog of Monomethyl auristatin E (MMAE) and can induce DC (dendritic cells) homing and activate cellular antitumor immune responses in patients.
Dolastatin 10 is a marine natural pentapeptide isolated from the Indian Ocean sea hare Dolabella auricularia. Recognized as one of the most potent naturally occurring antineoplastic agents, it effectively induces apoptosis in various tumor cells at nanomolar concentrations. Although its own clinical development was hindered by limited efficacy and neurotoxicity, its derivative, monomethyl auristatin E (MMAE), has been successfully utilized as a payload in antibody-drug conjugates (ADCs) like Adcetris® for treating lymphomas.| Targets |
The molecular target of dolastatin 10 is not explicitly stated in this study. The paper focuses on structural modifications (auristatins) and their anticancer activity, referencing the parent compound’s properties without detailing its specific target or providing IC50/Ki/EC50 values for dolastatin 10 itself in this context.
The direct molecular target of Dolastatin 10 is tubulin. It is an antimitotic agent that binds with high affinity to the vinca alkaloid binding domain on β-tubulin. This binding inhibits the polymerization of tubulin into microtubules, arresting the cell cycle at the G2/M phase and ultimately inducing apoptosis via the mitochondrial pathway. |
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| ln Vitro |
Dolastatin 10 is a distinct pentapeptide that was found in Dolabella aurillaryia, a type of sea hare. These in vitro results are similar to those obtained from similar human cell mini-panels with GI50 values of 10-5-10-6 μg/mL (10-2-10-3) for both dolastatin 10 and auristatin PE [2]. The anti-CD30 monoclonal antibody cAC10 is combined with the cytotoxic compound monomethyl auristatin E (MMAE), a synthetic analogue of the tubulin polymerization inhibitor dolastatin 10, to form the antibody-drug combination (ADC) [3].
Dolastatin 10 and auristatin PE (a close derivative) are referenced as having GI50 values of 10^-5 to 10^-6 µg/mL (10^-2 to 10^-3 nM) against a minipanel of human cancer cell lines. This is mentioned as a benchmark for comparing the newly synthesized auristatin analogues (TP, 2-AQ, 6-AQ). [2] Dolastatin 10 exhibits extremely potent growth inhibitory activity against various tumor cell lines in vitro. For instance, its IC₅₀ values are as low as 0.03 nM against murine L1210 leukemia cells, 0.059 nM against NCI-H69 small cell lung cancer cells, and 0.5 nM against human DU-145 prostate cancer cells. It also potently inhibits the proliferation of normal hematopoietic progenitor cells, with IC₅₀ values between 0.1 and 1 pg/mL, which is 25 to 100-fold lower than its antineoplastic concentration, indicating potential myelotoxicity. |
| ln Vivo |
In severe combined immunodeficiency (SCID) mouse xenograft models of ALCL or Hodgkin lymphoma, treatment with the ADC brentuximab vedotin (containing the dolastatin 10 analog MMAE) at 30 mg/kg showed no signs of toxicity. [3]
- In preclinical models of ALCL, the ADC brentuximab vedotin (containing the dolastatin 10 analog MMAE) exhibited dose-dependent antitumor activity, with complete regressions achieved using doses ≥0.5 mg/kg (with repeat dosing) and ≥1 mg/kg (with single dosing). [3] In vivo, Dolastatin 10 demonstrates significant antitumor activity in animal models. It prolonged the lifespan of mice in the P388 leukemia model. In a SCID mouse xenograft model of human B-cell chronic lymphocytic leukemia (WSU-CLL), Dolastatin 10 treatment resulted in a tumor growth inhibition rate (T/C) of 14% and a tumor growth delay (T-C) of 25 days, showing definite but non-curative activity. |
| Enzyme Assay |
Functional binding is assessed using purified tubulin via a tubulin polymerization assay. Purified porcine brain tubulin (1 mg/mL) is incubated in a glutamate-containing buffer with varying concentrations of Dolastatin 10 (e.g., 0 to 10 µM). Polymerization is followed by monitoring the increase in absorbance at 350 nm at 37°C. Dolastatin 10 inhibits polymerization in a concentration-dependent manner with an IC₅₀ of approximately 1.2 µM. Alternatively, a competitive binding assay using radiolabeled vinblastine ([³H]-vinblastine) incubated with tubulin can be used, where Dolastatin 10 competitively inhibits this binding, indicating its interaction at the vinca site.
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| Cell Assay |
The in vitro cytotoxic activity is primarily attributed to the antibody-drug conjugate brentuximab vedotin and its released payload MMAE (a dolastatin 10 analog). [3]
- The conjugate showed potent cytotoxic activity against CD30-expressing cells (IC50 < 10 ng/mL) but was 300-fold less potent against antigen-negative cells. [3] Cytotoxicity is determined using standard cell proliferation assays, e.g., with L1210 murine leukemia cells. Cells (e.g., 2×10⁵ cells/mL) are seeded in 96-well plates and treated with escalating concentrations of Dolastatin 10 (from 0.0001 nM to 100 nM) for 48-72 hours. Viable cells are then quantified using an MTT or CCK-8 kit, or DNA synthesis is assessed via [³H]-thymidine incorporation. The IC₅₀ is calculated from concentration-inhibition curves, with Dolastatin 10 achieving IC₅₀ values as low as 0.03 nM in L1210 cells. Treated cells should be examined by flow cytometry or morphology for cell cycle arrest and apoptosis. |
| Animal Protocol |
Antitumor activity is commonly evaluated using murine xenograft models. For example, human WSU-CLL cells are implanted subcutaneously into SCID mice. Treatment begins when tumors reach approximately 100 mm³. Dolastatin 10 is typically administered intravenously via the tail vein at doses ranging from 0.1 to 0.5 mg/kg (or ~1350 μg/m², the MTD in mice), often on a q4d×3 or similar intermittent schedule. Tumor growth inhibition (TGI) and tumor growth delay (T-C value) are calculated by measuring tumor volumes (length×width²/2) twice weekly. Body weight and clinical observations are also recorded to assess toxicity.
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| ADME/Pharmacokinetics |
The pharmacokinetics of Dolastatin 10 have been characterized in a Phase I clinical study. It fits a three-compartment model in vivo: a rapid distribution phase followed by a slower elimination phase. The mean terminal elimination half-life (t₁/₂γ) is 18.9 hours, with an intermediate half-life (t₁/₂β) of 0.99 hours. Significant inter- and intra-patient variability in plasma clearance was observed. The primary route of elimination is metabolism, with an N-dimethyl derivative detected as a metabolite in some patients, but its concentration never exceeded 2% of the parent drug.
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| Toxicity/Toxicokinetics |
In a Phase I clinical trial, the maximum tolerated dose (MTD) of the antibody-drug conjugate brentuximab vedotin (containing the dolastatin 10 analogue MMAE) was defined as 1.8 mg/kg (administered every 3 weeks). Dose-limiting toxicities (hyperglycemia, prostatitis, neutropenic fever) were observed at a dose of 2.7 mg/kg. [3] - One patient treated with a dose of 3.6 mg/kg developed fever, neutropenia, and sepsis and died 14 days after the first dose. [3] - Common adverse events associated with this antibody-drug conjugate (and therefore indirectly related to the payload mechanism) included peripheral sensory neuropathy, fatigue, nausea, neutropenia, and thrombocytopenia. [3]
The primary dose-limiting toxicity of Dolastatin 10 is myelosuppression, particularly granulocytopenia. In preclinical toxicology studies, the maximum tolerated doses (MTDs) in mice, rats, and dogs were approximately 1350 μg/m², 450 μg/m², and ≤400 μg/m², respectively, with the bone marrow identified as the primary target organ in all three species. In a Phase I clinical trial, dose-limiting granulocytopenia occurred in 33% of patients treated at the 300 μg/m² dose level. Common non-hematological toxicity included reversible peripheral neuropathy, which stalled its further development in Phase II trials. |
| References |
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| Additional Infomation |
Dolastatin 10 is a tetrapeptide isolated from the sea hare Dolabella auricularia. It is a potent anticancer agent that inhibits microtubule polymerization. It possesses multiple functions, including as an animal metabolite, a marine metabolite, an antitumor agent, an apoptosis inducer, and a microtubule destabilizer. It belongs to the 1,3-thiazole class of compounds and is a tetrapeptide. Its function is related to L-valine. Dolastatin 10 has been used in research trials for the treatment of various cancers, including sarcoma, leukemia, lymphoma, liver cancer, and kidney cancer. Dolastatin 10 has been reported to exist in sea hares (Dolabella auricularia), Symploca, and other organisms with relevant data. Dolastatin 10 is a pentapeptide, originally isolated from the marine mollusc Dolabella auricularia, and possesses potential antitumor activity. Dolatasstatin 10 binds to tubulin, inhibiting microtubule assembly, leading to the formation of tubulin aggregates and inhibiting mitosis. The drug also induces tumor cell apoptosis through a mechanism involving bcl-2, an oncoprotein overexpressed in some cancers. (NCI04)
Dolatasstatin 10 is a unique pentapeptide, originally isolated from the sea hare Dolabella auricularia. [2] - It has significant anticancer properties and has generated considerable interest in its closely related derivatives, osrestatin, which are suitable for clinical trials. [2] - As of the time of this publication, doralastatin 10 and three of its osrestatin analogues have entered Phase I to III human cancer clinical trials. [2] - This study explored structural modifications of the doralastatin 10 skeleton (phosphate and aminoquinoline conjugates) to construct water-soluble prodrugs (e.g., osrestatin TP salts) to improve its bioavailability and efficacy. The principle is that serum phosphatase can dephosphorylate these salts, thereby releasing the active drug into the cell. [2] |
| Molecular Formula |
C42H68N6O6S
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|---|---|
| Molecular Weight |
785.09092
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| Exact Mass |
784.492
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| Elemental Analysis |
C, 64.25; H, 8.73; N, 10.70; O, 12.23; S, 4.08
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| CAS # |
110417-88-4
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| Related CAS # |
160800-57-7 (Auristatin E, a synthetic analog of dolastatin 10); 123884-00-4 (Dolastatin 15); 163768-50-1 (Auristatin F, a synthetic analog of dolastatin 10); 2342568-65-2
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| PubChem CID |
9810929
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| SequenceShortening |
VV
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
903.6±65.0 °C at 760 mmHg
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| Flash Point |
500.3±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.537
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| LogP |
6.44
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
21
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| Heavy Atom Count |
55
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| Complexity |
1220
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| Defined Atom Stereocenter Count |
9
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| SMILES |
CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@@H]([C@@H](C)C(=O)N[C@@H](CC2=CC=CC=C2)C3=NC=CS3)OC)OC)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N(C)C
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| InChi Key |
OFDNQWIFNXBECV-VFSYNPLYSA-N
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| InChi Code |
InChI=1S/C42H68N6O6S/c1-13-28(6)37(47(10)42(52)35(26(2)3)45-40(51)36(27(4)5)46(8)9)33(53-11)25-34(49)48-22-17-20-32(48)38(54-12)29(7)39(50)44-31(41-43-21-23-55-41)24-30-18-15-14-16-19-30/h14-16,18-19,21,23,26-29,31-33,35-38H,13,17,20,22,24-25H2,1-12H3,(H,44,50)(H,45,51)/t28-,29+,31-,32-,33+,35-,36-,37-,38+/m0/s1
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| Chemical Name |
(S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N-((3R,4S,5S)-3-methoxy-1-((S)-2-((1R,2R)-1-methoxy-2-methyl-3-oxo-3-(((S)-2-phenyl-1-(thiazol-2-yl)ethyl)amino)propyl)pyrrolidin-1-yl)-5-methyl-1-oxoheptan-4-yl)-N,3-dimethylbutanamide
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| Synonyms |
NSC-376128; DLS-10; NSC376128; DLS10; Dolastatin 10; 110417-88-4; Dolastatin-10; NSC 376,128; EI946JT51X; NSC 376128; DLS 10
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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 Note: (1). This product is not stable in solution, please use freshly prepared working solution for optimal results. (2). Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
DMSO : ≥ 100 mg/mL (~127.37 mM)
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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 | 1.2737 mL | 6.3687 mL | 12.7374 mL | |
| 5 mM | 0.2547 mL | 1.2737 mL | 2.5475 mL | |
| 10 mM | 0.1274 mL | 0.6369 mL | 1.2737 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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