| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg | |||
| Other Sizes |
| Targets |
TAS4464 targets the NEDD8-activating enzyme (NAE), the E1 enzyme responsible for activating NEDD8 for conjugation to substrate proteins in the neddylation pathway. The compound demonstrates an IC50 of 0.955 nM for NAE inhibition and exhibits >400-fold selectivity over other E1 enzymes including ubiquitin-activating enzyme (UAE) and SUMO-activating enzyme (SAE). By selectively inhibiting NAE, TAS4464 blocks the neddylation of cullin proteins, thereby inactivating CRLs and leading to the accumulation of their substrates.
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| ln Vitro |
In 47 human cancer cell lines, TAS4464 therapy suppresses cullin neddylation, which in turn causes the buildup of CRL substrates (such as CDT1, p27), as well as phosphorylated IκBα.
In vitro, TAS4464 potently inhibits NAE with an IC50 of 0.955 nM, showing remarkable selectivity with >400-fold over UAE and SAE. Treatment with TAS4464 inhibits cullin neddylation and subsequently induces the accumulation of CRL substrates such as CDT1, p27, and phosphorylated IkappaBalpha in 47 human cancer cell lines. The compound exhibits superior antitumor activity with prolonged target inhibition in various cancer models. These in vitro effects lead to cell cycle arrest and apoptosis in cancer cells. |
| ln Vivo |
In vivo, TAS4464 demonstrates antitumor activity in diverse cancer models. Pharmacokinetic studies in male Balb/c mice have been conducted following intravenous administration of TAS4464 at 50 mg/kg. The compound exhibits prolonged target inhibition, which contributes to its superior antitumor efficacy. TAS4464 has been investigated in a Phase 1/2 clinical trial for patients with multiple myeloma or lymphoma (NCT02978235).
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| Enzyme Assay |
NAE enzyme activity assays are performed using purified recombinant NAE enzyme and NEDD8 substrate. The assay measures the formation of NEDD8-NAE thioester intermediates or the transfer of NEDD8 to the E2 enzyme Ubc12. TAS4464 is incubated with NAE, NEDD8, and ATP at varying concentrations, and the reaction is stopped after a defined incubation period. The amount of NEDD8-NAE or NEDD8-Ubc12 is detected by immunoblotting or using labeled NEDD8. IC50 values are calculated from concentration-response curves.
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| Cell Assay |
Cellular assays are performed using various human cancer cell lines. Cells are cultured and treated with TAS4464 at varying concentrations for defined time periods. Inhibition of neddylation is assessed by Western blot analysis for neddylated cullin proteins and accumulation of CRL substrates such as CDT1, p27, and phosphorylated IkappaBalpha. Cell viability and proliferation are measured using standard assays such as MTT, CellTiter-Glo, or colony formation assays. Apoptosis is assessed by measuring caspase activation, PARP cleavage, or Annexin V staining.
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| Animal Protocol |
In vivo efficacy studies are conducted in mouse xenograft models using human cancer cell lines. TAS4464 is administered via intravenous or oral routes at defined doses and schedules. Tumor growth is monitored by caliper measurements, and tumor volumes are calculated. Pharmacokinetic studies are performed in male Balb/c mice following intravenous administration at 50 mg/kg, with plasma samples collected at various time points for compound concentration analysis by LC-MS/MS.
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| ADME/Pharmacokinetics |
Pharmacokinetic profiles of TAS4464 have been characterized in preclinical models. Following intravenous administration of 50 mg/kg in male Balb/c mice, plasma concentrations are measured over time. The compound exhibits a pharmacokinetic profile consistent with prolonged target inhibition, contributing to its sustained antitumor activity. TAS4464 has been evaluated in a Phase 1/2 clinical trial (NCT02978235) for safety, pharmacokinetics, and efficacy in patients with multiple myeloma or lymphoma. TAS4464 is a small molecule with good solubility in DMSO (≥60 mg/mL).
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| Toxicity/Toxicokinetics |
TAS4464 has been evaluated in a Phase 1/2 open-label clinical trial (NCT02978235) for safety, pharmacokinetics, and efficacy in patients with multiple myeloma or lymphoma. Comprehensive toxicology data from clinical trials are not publicly available in the search results. As an investigational drug, TAS4464 is intended for research and clinical development purposes. Standard safety precautions should be followed when handling the compound.
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| References | |
| Additional Infomation |
TAS4464 is a highly potent and selective NEDD8-activating enzyme (NAE) inhibitor (IC50 = 0.955 nM, >400-fold selective over UAE and SAE). It inhibits cullin neddylation, leading to accumulation of CRL substrates and antitumor activity. TAS4464 has been investigated in a Phase 1/2 clinical trial for multiple myeloma and lymphoma (NCT02978235). The compound is for research use only and is not approved for therapeutic use outside of clinical trials.
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| Molecular Formula |
C21H23FN6O6S
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|---|---|
| Molecular Weight |
506.507326364517
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| Exact Mass |
506.138
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| CAS # |
1848959-10-3
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| Related CAS # |
TAS4464 hydrochloride;1848959-11-4
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| PubChem CID |
124121703
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
0.2
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
911
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| Defined Atom Stereocenter Count |
4
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| SMILES |
S(N)(NC[C@@H]1[C@H]([C@H]([C@H](N2C=C(C#CC3C(=CC=CC=3OCC)F)C3=C(N)N=CN=C23)O1)O)O)(=O)=O
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| InChi Key |
TZTRUHFXPVXWRD-QTQZEZTPSA-N
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| InChi Code |
InChI=1S/C21H23FN6O6S/c1-2-33-14-5-3-4-13(22)12(14)7-6-11-9-28(20-16(11)19(23)25-10-26-20)21-18(30)17(29)15(34-21)8-27-35(24,31)32/h3-5,9-10,15,17-18,21,27,29-30H,2,8H2,1H3,(H2,23,25,26)(H2,24,31,32)/t15-,17-,18-,21-/m1/s1
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| Chemical Name |
7H-Pyrrolo[2,3-d]pyrimidin-4-amine,
7-[5-[(aminosulfonyl)amino]-5-deoxy-beta-D-ribofuranosyl]-5-[2-(2-ethoxy-6-fluorophenyl)ethynyl]-
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| Synonyms |
TAS4464 TAS-4464 TAS 4464.
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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) |
DMSO : ~40 mg/mL (~78.97 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.95 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 20.0 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 mg/mL (3.95 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9743 mL | 9.8715 mL | 19.7429 mL | |
| 5 mM | 0.3949 mL | 1.9743 mL | 3.9486 mL | |
| 10 mM | 0.1974 mL | 0.9871 mL | 1.9743 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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