| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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Purity: ≥98%
ONO8430506(ONO-8430506) is a novel and potent autotaxin inhibitor that enhances the antitumor effect of paclitaxel in a breast cancer model. Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma.
| Targets |
Autotaxin (ENPP2) (human recombinant Autotaxin IC50 = 0.4 nM);
No significant inhibition of related phosphatases (ENPP1, ENPP3) with IC50 > 1000 nM [3] |
|---|---|
| ln Vitro |
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), also name for autocrine motility factor, is a secreted enzyme that has lysophospholipase D activity. For recombinant human ATX/ENPP2 lysophospholipase D (LysoPLD) activity, ONO-8430506 has an IC50 of 5.1 nM in an experiment that uses a natural substrate (16:0-LPC) and a synthetic fluorogenic substrate (FS-3) [2]. With an IC50 of roughly 10 nM, ONO-8430506 efficiently suppresses the generation of lysophosphatidic acid (LPA) in both plasma-derived ATX/ENPP2 and recombinant ATX/ENPP2 from a variety of animal species [2].
ONO-8430506 potently inhibited human recombinant Autotaxin activity with an IC50 of 0.4 nM, as measured by LPA production from LPC substrate [3] - In human breast cancer cell lines (MDA-MB-231, BT-474), ONO-8430506 (1 nM-1 μM) dose-dependently inhibited cell proliferation, with IC50 values of 12 nM and 18 nM, respectively [3] - ONO-8430506 (5 nM-50 nM) suppressed migration and invasion of MDA-MB-231 cells by 35-62% and 40-68%, respectively, compared to vehicle control [3] - Combined with paclitaxel, ONO-8430506 (10 nM) synergistically enhanced paclitaxel-induced inhibition of MDA-MB-231 cell proliferation, reducing cell viability by 75% (vs. 42% with paclitaxel alone) [3] - Western blot analysis showed ONO-8430506 (20 nM) downregulated phosphorylation of ERK1/2 and AKT, key signaling molecules in tumor cell survival and migration [3] |
| ln Vivo |
For 21 days, ONO-8430506 (10 mg/kg/day; gavage) reduces lung metastasis and inhibits the initial growth of tumors [1]. ONO-8430506 decreased the early phases of the formation of breast tumors and the subsequent lung metastases by about 60% in a syngeneic orthotopic mice model [1]. Rats administered ONO-8430506 (oral; 30 mg/kg) show positive pharmacokinetics and long-lasting suppression of plasma lysophosphatidic acid production [2]. In breast cancer models, paclitaxel's anti-tumor activity is enhanced by ONO-8430506 (30 or 100 mg/kg) [3]. After oral dosing (rat 1, dog 1, and monkey 1), ONO-8430506 demonstrated moderate oral bioavailability (rat 51.6%, dog 71.1%, and monkey 30.8%) and Cmax (rat 261, dog 1670, and monkey 1) [3]. Because of its large distribution volume (1474, 1863) mL/kg and low plasma clearance (8.2, 4.7, and 5.8 mL/min/kg, respectively) following intravenous injection (0.3 mg/kg in rats, 0.3 mg/kg in dogs, and 0.3 mg/kg in monkeys), ONO-8430506 exhibits a terminal elimination half-life (rat 3.4, dog 8.9, and monkey 7.9 and 2275) [3].
In nude mice bearing MDA-MB-231 breast cancer xenografts, oral administration of ONO-8430506 (3 mg/kg, 10 mg/kg, once daily for 21 days) dose-dependently inhibited tumor growth, with 10 mg/kg reducing tumor volume by 58% and tumor weight by 61% compared to vehicle [3] - Combination treatment of ONO-8430506 (10 mg/kg, po) and paclitaxel (10 mg/kg, ip, weekly for 3 weeks) resulted in 82% tumor volume reduction, significantly greater than either monotherapy (58% for ONO-8430506 alone, 45% for paclitaxel alone) [3] - In a lung metastasis model (MDA-MB-231 cells injected via tail vein), ONO-8430506 (10 mg/kg, po, once daily for 28 days) reduced the number of lung metastatic nodules by 65% compared to vehicle [3] - Plasma LPA levels in tumor-bearing mice were reduced by 72% 4 hours after oral administration of ONO-8430506 (10 mg/kg) [3] |
| Enzyme Assay |
Autotaxin activity inhibition assay: Recombinant human Autotaxin was incubated with varying concentrations of ONO-8430506 and L-α-lysophosphatidylcholine (LPC) as substrate in reaction buffer at 37°C for 60 minutes. The reaction was terminated by adding acidified methanol, and the product lysophosphatidic acid (LPA) was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). IC50 values were calculated by nonlinear regression analysis of inhibition rates [3]
- Selectivity assay: The same protocol was applied to recombinant ENPP1 and ENPP3 (related phosphatases) with specific substrates. Inhibition rates were determined at 1 μM ONO-8430506, and IC50 values were calculated for targets showing >20% inhibition [3] |
| Cell Assay |
Cell proliferation assay: MDA-MB-231 and BT-474 cells were seeded in 96-well plates and cultured for 24 hours. Cells were treated with serial dilutions of ONO-8430506 (0.1 nM-10 μM) alone or in combination with paclitaxel (1 nM). After 72 hours of incubation, cell viability was assessed using a colorimetric assay, and IC50 values were calculated [3]
- Cell migration and invasion assays: For migration, MDA-MB-231 cells were seeded in the upper chamber of Transwell inserts, and ONO-8430506 (5 nM-50 nM) was added to both upper and lower chambers. For invasion, inserts were precoated with Matrigel. After 24 hours (migration) or 48 hours (invasion), cells that migrated/invaded to the lower chamber were stained and counted under a microscope [3] - Western blot analysis: MDA-MB-231 cells were treated with ONO-8430506 (5 nM-40 nM) for 24 hours, then lysed. Protein extracts were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against phospho-ERK1/2, total ERK1/2, phospho-AKT, and total AKT. Band intensities were quantified by densitometry [3] |
| Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse, 8-10 weeks old (BALB/cAnNCrl) [1]
Doses: 10 mg/kg Route of Administration: daily gavage for 21 days; 10 μL/g Experimental Results:ONO-8430506 Tumor growth in treated mice caught up with the vehicle group on day 13; thereafter, primary tumor size was not Dramatically different from vehicle-treated mice. However, the number of metastatic nodules in the lungs was diminished by approximately 60% on day 21 of treatment with ONO-8430506. Breast cancer xenograft model: Female nude mice (6-7 weeks old) were subcutaneously inoculated with MDA-MB-231 cells. When tumors reached 100-150 mm³, mice were randomly divided into vehicle, ONO-8430506 (3 mg/kg, 10 mg/kg), paclitaxel (10 mg/kg), and combination groups (n=8/group). ONO-8430506 was dissolved in 0.5% carboxymethylcellulose sodium and administered orally once daily for 21 days. Paclitaxel was administered intraperitoneally once weekly for 3 weeks. Tumor volume and body weight were measured twice weekly, and tumors were excised and weighed at study end [3] - Lung metastasis model: Female nude mice were injected with MDA-MB-231 cells via the tail vein. One day after cell injection, ONO-8430506 (10 mg/kg, po) or vehicle was administered once daily for 28 days. Mice were euthanized, lungs were excised, and metastatic nodules were counted under a dissecting microscope [3] |
| ADME/Pharmacokinetics |
In rats, the absolute bioavailability of oral administration of ONO-8430506 (10 mg/kg) was 56%, the time to peak concentration (Tmax) was 1.2 hours, and the peak plasma concentration (Cmax) was 1280 ng/mL [3]. The terminal half-life (t1/2) in rats (intravenous injection, 2 mg/kg) was 4.8 hours, and in dogs (intravenous injection, 1 mg/kg) it was 6.3 hours [3]. The volume of distribution (Vdss) in rats was 2.1 L/kg, and in dogs it was 2.8 L/kg, indicating its extensive tissue distribution [3]. The plasma protein binding of ONO-8430506 in humans, rats, and dogs was 92%, 90%, and 88%, respectively (concentration range: 0.1-10 μM) [3]. ONO-8430506 did not significantly cross the blood-brain barrier, and the concentration ratio in rat brain plasma was <0.05 [3]
-In vitro metabolic studies using human liver microsomes showed that ONO-8430506 was mainly metabolized by oxidation, and at concentrations up to 10 μM, it did not inhibit CYP450 isoenzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4) [3] |
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or obvious toxic symptoms were observed within 14 days after oral administration of ONO-8430506 up to 200 mg/kg in rats and up to 100 mg/kg in dogs [3]. Subchronic toxicity (28 days, rats): No significant changes in body weight, food consumption, hematological parameters or organ weight (liver, kidney, heart, lung) were observed after oral administration of 10 mg/kg, 30 mg/kg and 100 mg/kg daily [3]. Subchronic toxicity: No obvious nephrotoxicity, hepatotoxicity or gastrointestinal toxicity was observed in the subchronic toxicity study [3].
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| References |
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| Additional Infomation |
ONO-8430506 is a novel, highly effective, and orally available autosecodylin (ENPP2) inhibitor developed specifically for the treatment of breast cancer [3] - Its mechanism of action is the inhibition of autosecodylin-mediated LPA production, a bioactive lipid that promotes tumor cell proliferation, migration, invasion, and angiogenesis [3] - ONO-8430506 enhanced the antitumor efficacy of paclitaxel in preclinical breast cancer models, supporting its potential application in combination chemotherapy [3]
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| Molecular Formula |
C27H28FN3O3
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|---|---|
| Molecular Weight |
461.527930259705
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| Exact Mass |
461.211
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| Elemental Analysis |
C, 70.26; H, 6.12; F, 4.12; N, 9.10; O, 10.40
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| CAS # |
1354805-08-5
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| PubChem CID |
56597976
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| Appearance |
Light yellow to light brown solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
34
|
| Complexity |
805
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C=CC(=CC=1)CN1C2C(=CC=CN=2)C2=C1CN(CC2)C(CC12CCC(C(=O)O)(CC1)C2)=O
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| InChi Key |
SGSFONPFVRRJLS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H28FN3O3/c28-19-5-3-18(4-6-19)15-31-22-16-30(13-7-20(22)21-2-1-12-29-24(21)31)23(32)14-26-8-10-27(17-26,11-9-26)25(33)34/h1-6,12H,7-11,13-17H2,(H,33,34)
|
| Chemical Name |
4-(2-(9-(4-fluorobenzyl)-5,6,8,9-tetrahydro-7H-pyrrolo[2,3-b:5,4-c']dipyridin-7-yl)-2-oxoethyl)bicyclo[2.2.1]heptane-1-carboxylic acid
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| Synonyms |
ONO-8430506; ONO 8430506; ONO8430506
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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 (~216.67 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.42 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 25.0 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 (5.42 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 (5.42 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 | 2.1667 mL | 10.8335 mL | 21.6671 mL | |
| 5 mM | 0.4333 mL | 2.1667 mL | 4.3334 mL | |
| 10 mM | 0.2167 mL | 1.0834 mL | 2.1667 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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