| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 50mg | |||
| Other Sizes |
| Targets |
AKR1C3 (aldo-keto reductase family 1 member C3), DNA.
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| ln Vitro |
OBBI-3424 exhibits strong cytotoxicity against the H460 lung cancer cell line with an IC50 of 4.0 nM. OBI-3424 has strong cytotoxicity, with IC50 values in the low nM range, especially against T-ALL cell lines that express high levels of AKR1C3 [1]. Strong cell killing is also exerted by OBI-3424 against ALL PDXs; the median IC50 values for B-ALL, T-ALL, and ETP-ALL were 60.3 nM, 9.7 nM, and 31.5 nM, respectively[1].
OBI-3424 is a prodrug that is selectively activated by AKR1C3 to a potent DNA alkylating agent. AKR1C3 is overexpressed in many cancer types, particularly in liver cancer, non-small cell lung cancer, gastric cancer, renal cancer, and castrate-resistant prostate cancer (CRPC). The active metabolite causes DNA cross-linking, leading to cell death. The compound has demonstrated efficacy in preclinical models of T-cell acute lymphoblastic leukemia (T-ALL). It is a novel bis-alkylating agent. |
| ln Vivo |
Treatment with OBI-3424 (0.5-2.5 mg/kg; ip; once weekly; for 3 weeks) causes regressions in mice with Parkinson's disease and prolongs the event-free lifespan of the mice[1].
OBI-3424 has demonstrated efficacy in preclinical models of T-cell acute lymphoblastic leukemia (T-ALL) and other AKR1C3-positive tumors. In xenograft mouse models, it significantly inhibits tumor growth and induces tumor regression. It is currently in clinical trials for patients with advanced solid tumors and for relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL). |
| Enzyme Assay |
Assay: In vitro AKR1C3 enzyme activity assay. Protocol: Recombinant AKR1C3 is incubated with varying concentrations of OBI-3424 and its cofactor NADPH in assay buffer. The conversion of OBI-3424 to its intermediate metabolite is measured by monitoring the decrease in NADPH fluorescence (excitation 340 nm, emission 460 nm) or by LC-MS quantification of the metabolite. The rate of reaction is calculated, and the compound's status as a substrate is confirmed. IC50 of OBI-3424 against AKR1C3 is not applicable; it is a substrate.
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| Cell Assay |
Cells: Cancer cell lines with high AKR1C3 expression (e.g., some HCC, CRPC, and T-ALL lines). Protocol: Cells are treated with OBI-3424 (0.1-1000 nM) for 48-72 hours. Cell viability is measured by MTT or CellTiter-Glo. The selectivity index is determined by comparing viability in AKR1C3-high vs. AKR1C3-low cell lines. DNA cross-linking is measured by the comet assay or by quantification of interstrand crosslinks. Apoptosis is assessed by caspase-3/7 activation and PARP cleavage.
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| Animal Protocol |
Animal/Disease Models: Female NSG mice (20-25 g) bearing patient-derived xenografts (PDX)[1]
Doses: 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg Route of Administration: intraperitoneal (ip)injection ; once weekly; for 3 weeks Experimental Results: Resulted in prolongation of mouse event-free survival. Animal Model: Xenograft mouse models of AKR1C3-positive tumors (e.g., T-ALL, HCC). Protocol: Mice bearing subcutaneous tumors are treated with OBI-3424 via intraperitoneal (IP) or intravenous (IV) injection at doses of 5-20 mg/kg once weekly for 2-4 weeks. Tumor volume is measured twice weekly. At study endpoint, tumors are collected for PD analysis (DNA crosslinking, apoptosis). Efficacy is determined by TGI and tumor regression. Body weight is monitored for safety. |
| ADME/Pharmacokinetics |
OBI-3424 is a prodrug that is rapidly absorbed and distributed. It is activated specifically in AKR1C3-expressing cells, leading to localized production of the active DNA alkylating agent. This activation restricts the active compound's exposure to normal tissues, potentially improving the therapeutic index. The parent drug has a half-life of 1-2 hours in plasma, while the active metabolite has a very short half-life (minutes), limiting systemic toxicity. The compound is administered IV or IP in preclinical models.
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| Toxicity/Toxicokinetics |
In preclinical models, OBI-3424 was well-tolerated at doses up to 20 mg/kg (IV) weekly, with no significant body weight loss or overt organ toxicity reported. Because the active metabolite is generated only in AKR1C3-expressing cells, systemic toxicity is expected to be lower than traditional alkylating agents. However, as a DNA alkylating agent, high doses could cause myelosuppression, gastrointestinal toxicity, and secondary malignancies.
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| References | |
| Additional Infomation |
OBI-3424 is being investigated in the clinical trial NCT04315324 (a study testing the Akr1c3-activated prodrug OBI-3424 in patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL)). The AKR1C3-activated prodrug AST-3424 is a small molecule nitrophenyl ketone reductase 1C3 (AKR1C3) activated prodrug, a prodrug of N,N'-bis(ethylenephosphoramide) (a DNA dialkylating agent) with potential antitumor activity. After intravenous injection, the AKR1C3-activated prodrug AST-3424 is converted to its active form by AKR1C3. AKR1C3 is upregulated in certain tumor cell types but not in normal healthy cells. The active metabolite selectively binds to and alkylates DNA in AKR1C3-overexpressing tumor cells, leading to DNA base mismatches, interstrand crosslinks, and inhibition of DNA repair and synthesis, ultimately resulting in cell cycle arrest and apoptosis. Because AKR1C3 expression is limited to tumor cells, AST-3424 is selectively converted to its active metabolite only in tumor cells, while not in normal healthy tissues; this makes the alkylating agent more cytotoxic in tumor cells while reducing its overall toxicity.
OBI-3424 (also known as AST-3424 or TH-3424) is a first-in-class AKR1C3-activated prodrug. It is designed to be a targeted chemotherapy, selectively killing cancer cells that overexpress AKR1C3 while sparing normal cells. It has entered Phase 1/2 clinical trials (NCT03592264 for advanced solid tumors; NCT04315324 for T-ALL). The compound was licensed from Threshold Pharmaceuticals to OBI Pharma. It is not FDA-approved but is in clinical development. |
| Molecular Formula |
C21H25N4O6P
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|---|---|
| Molecular Weight |
460.420165777206
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| Exact Mass |
460.15
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| Elemental Analysis |
C, 54.78; H, 5.47; N, 12.17; O, 20.85; P, 6.73
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| CAS # |
2097713-68-1
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| PubChem CID |
126961329
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| Appearance |
Solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
737
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@H](C1=CC(=C(C=C1)[N+](=O)[O-])OC2=CC=CC(=C2)C(=O)N(C)C)OP(=O)(N3CC3)N4CC4
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| InChi Key |
NWGZZGNICQFUHV-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C21H25N4O6P/c1-15(31-32(29,23-9-10-23)24-11-12-24)16-7-8-19(25(27)28)20(14-16)30-18-6-4-5-17(13-18)21(26)22(2)3/h4-8,13-15H,9-12H2,1-3H3/t15-/m1/s1
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| Chemical Name |
3-[5-[(1R)-1-[bis(aziridin-1-yl)phosphoryloxy]ethyl]-2-nitrophenoxy]-N,N-dimethylbenzamide
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| Synonyms |
AST 3424; AST-3424; AST3424; OBI 3424; OBI3424; OBI-3424
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 : ~50 mg/mL (~108.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1719 mL | 10.8596 mL | 21.7193 mL | |
| 5 mM | 0.4344 mL | 2.1719 mL | 4.3439 mL | |
| 10 mM | 0.2172 mL | 1.0860 mL | 2.1719 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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