| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
Traditional Cytotoxic Agents
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| ln Vitro |
Mipsagargin (G-202) is 57 times more potent against PSMA-producing LNCaP cells (IC50=5351 nM) than it is against PSMA-nonproducing TSU cells (IC50=191 nM)[2].
In addition, Mipsagargin (G202) was completely stable to hydrolysis in human plasma; in fact, the ability to hydrolyze Mipsagargin (G202) was relatively PSMA specific, as G202 was not appreciably hydrolyzed after incubation with a variety of other purified proteases[2].To determine whether nonspecific cellular uptake could be prevented by the 5–amino acid peptide in G202, we loaded PSMA-nonproducing TSU bladder cancer cells with a calcium-sensitive dye and exposed the cells to either 12ADTβAsp (200 nM) or G202 (5 mM) (6). Exposure of the PSMA-nonproducing TSU bladder cancer cells to 12ADTβAsp produced a rapid maximal elevation in intracellular Ca2+ up to 400 nM (Fig. 3E). In contrast, exposure of the same cells to 25-fold higher concentrations of G202 resulted in no appreciable increase in intracellular calcium (Fig. 3F). To confirm that Mipsagargin (G202) displayed selective toxicity to PSMA-producing cells, we compared the cytotoxic effects of Mipsagargin (G202) to those of the PSMA-nonhydrolyzing 12ADTβAsp-GluγGluγGlu-Asp in the PSMA-producing LNCaP human prostate cancer line and the PSMA-nonproducing TSU cell line. In this assay, the concentration that inhibited growth by 50% in cell proliferation assays (IC50) for the nonhydrolyzed prodrug was in the micromolar range against both cell lines (Fig. 3G). In contrast, the IC50 for G202 against the PSMA-nonproducing TSU cells was 57-fold higher than that for the PSMA-producing LNCaP cells (Fig. 3G). Finally, G202-induced growth inhibition of LNCaP cells could be blocked by the addition of 2-(phosphonomethyl)-pentanedioic acid (PMPA), a potent PSMA inhibitor, further confirming the PSMA requirement for activation of the prodrug in vitro [2] |
| ln Vivo |
On its own, mipagargin (G-202; 56 mg/kg; twice daily; 49 days) can significantly (>50%) reduce tumor growth. When daily dosage of the oral HDAC4 inhibitor Tasquinimod is added, this regression stabilizes[1].
Over the course of 30 days, intact mice treated with Mipsagargin (G202) (56 mg/kg/day for three days in a row) show an average regression of approximately 50% in LNCaP xenografts. A single 3-day course of Mipsagargin (G202) is also observed to have significant antitumor effects against MDA-PCa2b and CWR22R-H up to ≥30 days later[2]. In BALB/c mice, Mipsagargin (G202) (67 mg/kg; IV) has a half-life of 4.9 hours[2]. This suggestion is consistent with our earlier report that the therapeutic response of MCF-7 human breast cancer xenografts in estrogen-supplemented female mice to daily ×2 IV injections of 56 mg/kg/dose (i.e., 40 μmoles/kg/dose) Mipsagargin (G202)alone is able to produce significant (>50%) tumor regression. This regression is stabilized when combined with daily dosing with the oral HDAC4 inhibitor, Tasquinimod (TasQ; Figure 7E), which has been documented to inhibit autophagy [85]. These results warrant the clinical testing of a combination of daily oral TasQ with episodic IV dosing of Mipsagargin. In these preclinical xenograft studies, Mipsagargin, even as a single agent, induces tumor regression when given at its MTD of 56 mg/kg/dose (i.e., 40 μmoles/kg/dose). [1] |
| Enzyme Assay |
PSMA prodrug hydrolysis[2]
Prodrugs were incubated with 10 μM Fc-PSMA in tris buffer, containing 0.01 mM CoCl2. Aliquots were removed at various time points and analyzed by high-performance LC with 0.1% trifluoroacetic acid (TFA) in water as solvent A and 0.1% TFA in acetonitrile as solvent B. A gradient of 40% B to 100% B over 25 min was used to analyze cleavage products. Each hydrolysis product was identified by co-elution and confirmed by MS.[2] Calcium measurements and SERCA pump assays[2] Determination of intracellular free calcium levels was performed with the ratiometric method in a cuvette assay with 7.5 μM fura-2-acetoxymethyl ester (Molecular Probes)–loaded TSU cells as previously described. SERCA pump assays were performed with microsomes from rabbit skeletal muscle as previously described. The SERCA activity was measured with a coupled enzyme assay as the rate of adenosine 5′-triphosphate hydrolysis as previously described.[2] Crystal structure determination[2] Procedures for solubilization and crystallization of the 12ADTβAsp complex of rabbit SERCA1a, as well as for crystal stabilization and mounting, were essentially as described previously for other TG derivatives and are described in detail in the Supplementary Materials (Methods and table S2) |
| Cell Assay |
Cytotoxicity assays[2]
To determine cytotoxic activity of prodrugs, clonal survival assays were performed with PSMA-negative TSU human bladder cancer and PSMA-positive LNCaP human prostate cancer cells as previously described. |
| Animal Protocol |
Animal Model: Mice with human breast cancers MCF-7 growing[1]
Dosage: 56 mg/kg Administration: IV; 2 daily; 49 days Result: produced a notable (>50%) tumor regression on its own. When daily dosage of the oral HDAC4 inhibitor Tasquinimod (10 mg/kg/d; oral) was added, this regression stabilized. In vivo studies[2] Maximum tolerated dose (single intravenous dose) was determined and used to perform pharmacokinetic studies. Single-dose pharmacokinetics were assessed by noncompartmental analysis. The AUC from time zero to infinity (AUC0–∞) was calculated with the linear trapezoidal method. The terminal half-life (t1/2) was determined from the terminal slope (Ke) on a log-linear plot of concentration versus time. Biodistribution studies were performed on tumor-bearing mice by harvesting tissues (liver, kidney, skeletal muscle, brain, and tumor) from mice (n = 3) at varying time points after single or multiple intravenous injections of Mipsagargin (G202). (Analytical methods for processing, extracting, and analyzing plasma and tissue drug concentrations are included as supplemental information.)[2] In vivo efficacy studies[2] LNCaP, MDA-PCa2b, or SN12C (2 × 106) cells in 100 μl of Matrigel were inoculated into the flank of 6-week-old male nude mice. MCF-7 cells (2 × 106) were injected into the flanks of female nude mice pretreated with subcutaneous estrogen pellet according to the previously described method. CWR22R-H xenografts were generated by subcutaneous inoculation of 10 mg of minced CWR22R-H tumor in Matrigel as previously described. Statistical analysis of differences in tumor volumes and weights between Mipsagargin (G202) and vehicle controls was performed with Student's t test, and P values of <0.05 were reported in the text. |
| ADME/Pharmacokinetics |
Phase I clinical trial aimed to evaluate the safety, tolerability, and pharmacokinetic characteristics of intravenous mipsagargin in patients with locally advanced or metastatic solid tumors who were unresponsive to or had no standard therapy available. This study established a Phase II recommended dose-on-dose (RP2D) regimen: 40 mg/m² of mipsagargin administered intravenously over 1 hour on day 1, followed by RP2D infusions (66.8 mg/m² or 1.58 mg/kg) on days 2 and 3 of each 28-day cycle, with routine medication and prophylactic hydration performed before each infusion. Dose-limiting toxicities of mipsagargin included hypersensitivity reactions occurring on day 1 of the infusion cycle and a reversible increase in serum creatinine, which returned to normal before the end of the treatment cycle. At this infusion dose, the tissue distribution half-life (T1/2-α) of miprosagargin is estimated to be 2 hours, and the steady-state volume of distribution (Vss) is 5 L/m2 (i.e., 0.135 L/kg) [80]. This Vss is substantially equivalent to the extracellular fluid volume in humans (i.e., 7.3 L/m2 or 0.2 L/kg), which is consistent with its inability to enter normal tissues. Its elimination half-life (T1/2) is 21 hours.
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| References |
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| Additional Infomation |
Mipsagargin has been used in clinical trials for the treatment of various cancers, including prostate cancer, prostate tumors, advanced solid tumors, glioblastoma multiforme, and hepatocellular carcinoma. Mipsagargin is a soluble carotenoid prodrug containing a cytotoxic analogue of carotenoid, 8-O-(12-aminododecanoyl)-8-O-butyryl carotenoid (12-ADT). This analogue is linked to a targeting peptide containing aspartic acid via a carboxyl group, exhibiting potential antitumor activity. After intravenous injection, Mipsagargin targets prostate-specific membrane antigen (PSMA), a type II membrane carboxypeptidase overexpressed in prostate cancer cells and the angiogenesis of most solid tumors, but not in normal blood vessels. Subsequently, Mipsagargin is hydrolyzed to the active cytotoxic carotenoid analogue 12-ADT-Asp. 12-ADT binds to and blocks the activity of the sarcoplasmic/endoplasmic reticulum calcium pump (SERCA), thereby increasing cytoplasmic calcium ion concentration and ultimately inducing apoptosis. G-202 may inhibit tumor growth by blocking the nutrient supply to tumor cells. Compared with the use of carotenoids alone, the carotenoid prodrug G-202 can achieve higher concentrations of the active ingredient at the tumor site while avoiding systemic toxicity.
|
| Molecular Formula |
C66H100N6O27
|
|---|---|
| Molecular Weight |
1409.52
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| Exact Mass |
1408.66
|
| Elemental Analysis |
C, 56.24; H, 7.15; N, 5.96; O, 30.65
|
| CAS # |
1245732-48-2
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| Related CAS # |
1245732-48-2;1627852-87-2 (Trifluoroa cetate);
|
| PubChem CID |
24772106
|
| Sequence |
Asp-{Ggu}-{Ggu}-{Ggu}-{Ggu}
|
| SequenceShortening |
D{Ggu}-{Ggu}-{Ggu}-{Ggu}
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| Appearance |
Solid powder
|
| LogP |
-0.4
|
| Hydrogen Bond Donor Count |
13
|
| Hydrogen Bond Acceptor Count |
28
|
| Rotatable Bond Count |
50
|
| Heavy Atom Count |
99
|
| Complexity |
2990
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| Defined Atom Stereocenter Count |
13
|
| SMILES |
CCCCCCCC(=O)O[C@H]1[C@H]2C(=C([C@@H]1OC(=O)/C(=C\C)/C)C)[C@H]3[C@]([C@H](C[C@]2(C)OC(=O)C)OC(=O)CCCCCCCCCCCNC(=O)C[C@@H](C(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O)C(=O)O)C(=O)O)N)([C@](C(=O)O3)(C)O)O
|
| InChi Key |
UPYNTAIBQVNPIH-ODMLWHIESA-N
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| InChi Code |
InChI=1S/C66H100N6O27/c1-8-10-11-17-20-24-51(81)96-55-53-52(37(4)54(55)97-62(91)36(3)9-2)56-66(94,65(7,93)63(92)98-56)44(35-64(53,6)99-38(5)73)95-50(80)23-21-18-15-13-12-14-16-19-22-33-68-48(77)34-39(67)57(82)72-43(61(89)90)27-31-47(76)70-41(59(85)86)25-29-45(74)69-40(58(83)84)26-30-46(75)71-42(60(87)88)28-32-49(78)79/h9,39-44,53-56,93-94H,8,10-35,67H2,1-7H3,(H,68,77)(H,69,74)(H,70,76)(H,71,75)(H,72,82)(H,78,79)(H,83,84)(H,85,86)(H,87,88)(H,89,90)/b36-9-/t39-,40-,41-,42-,43-,44-,53+,54-,55-,56-,64-,65+,66+/m0/s1
|
| Chemical Name |
InChI=1S/C66H100N6O27/c1-8-10-11-17-20-24-51(81)96-55-53-52(37(4)54(55)97-62(91)36(3)9-2)56-66(94,65(7,93)63(92)98-56)44(35-64(53,6)99-38(5)73)95-50(80)23-21-18-15-13-12-14-16-19-22-33-68-48(77)34-39(67)57(82)72-43(61(89)90)27-31-47(76)70-41(59(85)86)25-29-45(74)69-40(58(83)84)26-30-46(75)71-42(60(87)88)28-32-49(78)79/h9,39-44,53-56,93-94H,8,10-35,67H2,1-7H3,(H,68,77)(H,69,74)(H,70,76)(H,71,75)(H,72,82)(H,78,79)(H,83,84)(H,85,86)(H,87,88)(H,89,90)/b36-9-/t39-,40-,41-,42-,43-,44-,53+,54-,55-,56-,64-,65+,66+/m0/s1
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| Synonyms |
G-202; G 202; G202; 1245732-48-2; G-202; Mipsagargin [USAN:INN]; UNII-Q032I35QMX; Q032I35QMX; Mipsagargin [INN]; Mipsagargin (USAN/INN); Mipsagargin
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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 | 0.7095 mL | 3.5473 mL | 7.0946 mL | |
| 5 mM | 0.1419 mL | 0.7095 mL | 1.4189 mL | |
| 10 mM | 0.0709 mL | 0.3547 mL | 0.7095 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01777594 | Completed | Drug: G-202 | Advanced Adult Hepatocellular Carcinoma |
GenSpera,Inc. | January 2013 | Phase 2 |
| NCT02067156 | Completed | Drug: G-202 | Glioblastoma Multiforme | GenSpera,Inc. | February 2014 | Phase 2 |
| NCT02876003 | Withdrawn | Drug: G-202 | Glioblastoma | GenSpera, Inc. | September 2016 | Phase 2 |
| NCT01056029 | Completed | Drug: G-202 | Advanced Solid Tumors | GenSpera, Inc. | January 2010 | Phase 1 |
| NCT02607553 | Completed | Drug: G-202 | Clear Cell Renal Cell Carcinoma | GenSpera, Inc. | June 2016 | Phase 2 |
| NCT02381236 | Completed | Drug: G-202 | Prostatic Neoplasms | GenSpera, Inc. | February 2016 | Phase 2 |
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