| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
The primary targets of Sirpiglenastat are glutamine-utilizing enzymes, as its active metabolite DON irreversibly inhibits several glutamine-dependent amidotransferases. These enzymes are critical for nucleotide synthesis, amino acid production, and other biosynthetic pathways that cancer cells rely on for rapid proliferation. By blocking glutamine metabolism, the prodrug disrupts essential metabolic processes, leading to tumor cell death and enhanced immune surveillance.
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| ln Vitro |
Treatment with siropilenastat (DRP-104) exhibits extensive effects on immune cell modulation, such as enhanced T, NK, and macrophages. Pro-tumorigenic cytokines including VEGF and KC (IL-8) are reduced by sirpiglenastat[1].
In vitro, Sirpiglenastat decreases the viability of P493B lymphoma cells with an EC50 of approximately 10 µM. As a glutamine antagonist, it effectively blocks the utilization of glutamine, a key nutrient for many cancer cells, causing metabolic stress and subsequent cell death. The compound also promotes the expression of major histocompatibility complex class I (MHC-I) on tumor cells, which enhances their recognition by the immune system. These effects are concentration-dependent and correlate with the degree of glutamine deprivation. |
| ln Vivo |
At day 12, 90% tumor growth inhibition is seen in CT26 bearing mice treated with Sirpiglenastat (DRP-104) (0.5 mg/kg; sc; once daily; for five days). 36 days are the median survival time[1]. In the H22 model, therapy with sirpiglenastat (0.5 mg/kg; sc) effectively suppresses tumor growth[1].
In vivo, Sirpiglenastat has demonstrated significant tumor growth inhibition in mouse models. For example, in CT26-bearing mice, subcutaneous administration of the prodrug at a dose of 0.5 mg/kg once daily for five days resulted in substantial tumor regression. Its efficacy is attributed to both direct metabolic disruption of cancer cells and the activation of antitumor immunity, as evidenced by increased infiltration of cytotoxic T cells into the tumor microenvironment. These findings support its potential as a novel cancer therapeutic. |
| Enzyme Assay |
The in vitro activity of Sirpiglenastat is typically assessed using cell viability assays. Cancer cell lines, such as P493B lymphoma cells, are seeded in 96-well plates and treated with varying concentrations of the compound (e.g., 0.1–100 µM) for 72 hours. Cell viability is then measured using a luminescent ATP-based assay, such as CellTiter-Glo, to generate a dose-response curve and determine the EC50 value. Parallel experiments measure glutamine consumption and metabolite levels to confirm target engagement.
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| Cell Assay |
To evaluate cellular effects, cancer cells are treated with Sirpiglenastat and analyzed for changes in metabolism and immune phenotype. Metabolic profiling using LC-MS/MS quantifies levels of glutamine and downstream metabolites like glutamate and alpha-ketoglutarate. Flow cytometry is employed to measure MHC-I surface expression and markers of apoptosis. Additionally, co-culture experiments with immune cells assess the compound's ability to enhance T-cell-mediated killing of tumor cells.
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| Animal Protocol |
Animal/Disease Models: CT26 bearing mice[1]
Doses: 0.5 mg/kg Route of Administration: sc; one time/day; for 5 days Experimental Results: demonstrated tumor growth inhibition in mice. In vivo efficacy is evaluated in syngeneic mouse tumor models, such as CT26 colon carcinoma-bearing mice. Animals are treated with Sirpiglenastat via subcutaneous injection at doses like 0.5 mg/kg once daily for five consecutive days. Tumor growth is monitored by caliper measurements, and at study endpoint, tumors are harvested for immunohistochemical analysis of immune cell infiltration and for metabolomic profiling to confirm on-target effects. |
| ADME/Pharmacokinetics |
As a prodrug of DON, Sirpiglenastat is designed to improve the pharmacokinetic profile by targeting the release of the active drug to the tumor site. The compound has a molecular weight of 441.48 and is administered subcutaneously in preclinical studies. While specific PK parameters are not widely published, the prodrug strategy aims to reduce systemic exposure to DON, thereby minimizing off-target toxicity while maintaining efficacious concentrations in the tumor.
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| Toxicity/Toxicokinetics |
Preclinical toxicological data indicate that Sirpiglenastat is better tolerated than DON due to its tumor-selective activation. However, as a glutamine antagonist, it may still cause gastrointestinal and hematological toxicities at higher doses. In clinical trials, adverse events are being monitored closely. The compound is not approved for human use, and its safety profile is currently being characterized in phase I/II studies for advanced solid tumors.
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| References |
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| Additional Infomation |
Sirpiglenastat, also known as DRP-104, is a prodrug of [6-diazo-5-oxo-L-leucine] (DON), a broad-spectrum glutamine antagonist. It is currently undergoing clinical trials (NCT04471415, a study of DRP-104 in adult patients with advanced solid tumors). Sirpiglenastat is a broad-spectrum glutamine antagonist with potential immunomodulatory and antitumor activities. After administration, the active ingredient of Sirpiglenastat, DON (6-diazo-5-oxo-L-leucine), irreversibly inhibits multiple enzymes involved in glutamine metabolism. Blocking glutamine metabolism inhibits the proliferation of rapidly growing tumor cells and induces cell death. Unlike normal healthy cells, glutamine-dependent tumors are highly dependent on the conversion of endogenous and exogenous glutamine into glutamate and its metabolites to provide energy and generate the macromolecular synthetic raw materials required for cell growth and survival. Furthermore, blocking glutamine metabolism leads to glutamine accumulation within tumor cells and increases glutamine concentration in the tumor microenvironment (TME) after tumor cell death. Since glutamine is crucial for T cell generation, DON may also enhance T cell proliferation and activation in the TME, thereby further killing tumor cells. sirpiglenastat is primarily converted to the active ingredient DON within tumor cells, allowing healthy cells to metabolize glutamine, potentially mitigating adverse effects.
Sirpiglenastat (DRP-104) is an investigational agent developed by Dracen Pharmaceuticals. It represents a novel approach to cancer therapy by combining metabolic targeting with immune modulation. The prodrug design addresses the historical toxicity issues of DON, making it a promising candidate for clinical translation. It is currently being evaluated in clinical trials for non-small cell lung cancer and other solid tumors with high glutamine dependence. |
| Molecular Formula |
C22H27N5O5
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|---|---|
| Molecular Weight |
441.480284929276
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| Exact Mass |
441.201
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| CAS # |
2079939-05-0
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| PubChem CID |
137308771
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| Appearance |
Off-white to yellow solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
32
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| Complexity |
749
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C(C1=CNC2=CC=CC=C12)[C@H](NC(=O)C)C(=O)N[C@@H](CCC(=O)C=[N+]=[N-])C(=O)OC(C)C
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| InChi Key |
LQNMCWOJACNQQM-PMACEKPBSA-N
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| InChi Code |
InChI=1S/C22H27N5O5/c1-13(2)32-22(31)19(9-8-16(29)12-25-23)27-21(30)20(26-14(3)28)10-15-11-24-18-7-5-4-6-17(15)18/h4-7,11-13,19-20,24H,8-10H2,1-3H3,(H,26,28)(H,27,30)/t19-,20-/m0/s1
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| Chemical Name |
propan-2-yl (2S)-2-[[(2S)-2-acetamido-3-(1H-indol-3-yl)propanoyl]amino]-6-diazo-5-oxohexanoate
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (226.51 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 | 2.2651 mL | 11.3255 mL | 22.6511 mL | |
| 5 mM | 0.4530 mL | 2.2651 mL | 4.5302 mL | |
| 10 mM | 0.2265 mL | 1.1326 mL | 2.2651 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.
Link: https://clinicaltrials.gov/ct2/show/NCT07430202
Conditions:Liver Cancer (Fibrolamellar Hepatocellular Cancer (FLC))Link: https://clinicaltrials.gov/ct2/show/NCT06027086
Conditions:Fibrolamellar Hepatocellular CarcinomaLink: https://clinicaltrials.gov/ct2/show/NCT07249372
Conditions:Non Small Cell Lung Cancer
Title:Study to Investigate DRP-104 in Adults With Advanced Solid Tumors
Status:Terminated
updateDate:2023-06-12
Ctid:NCT04471415
Link: https://clinicaltrials.gov/ct2/show/NCT04471415
Conditions:Advanced Solid Tumor|Non Small Cell Lung Cancer MetastaticProducts are for research use only; We do not sell to patients
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