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| Targets |
(R)-FT671 targets ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme that removes ubiquitin from target proteins, regulating their stability and function. USP7 plays a critical role in the p53 pathway by deubiquitinating MDM2, a negative regulator of p53. By inhibiting USP7 with an IC50 of 52 nM and a Kd of 65 nM, (R)-FT671 destabilizes MDM2, leading to increased p53 levels and activation of p53 target genes. This results in the induction of p21 and inhibition of tumor growth.
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| ln Vitro |
In vitro, (R)-FT671 functions as a potent, non-covalent, and selective inhibitor of USP7 with an IC50 of 52 nM and a Kd of 65 nM. By inhibiting USP7, the compound destabilizes USP7 substrates including MDM2, increasing levels of p53. This results in the transcription of p53 target genes, inducing the tumour suppressor p21. The compound's activity is typically evaluated using enzyme activity assays with purified USP7 and cellular assays measuring p53 and p21 levels.
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| ln Vivo |
In vivo, (R)-FT671 has been studied for its anti-tumor activity. By inhibiting USP7 and activating the p53 pathway, the compound induces tumor suppression. As the R-isomer of FT671, it shares the pharmacological properties of FT671. However, specific in vivo efficacy data for (R)-FT671, including dosing regimens and animal models, are not extensively detailed in the available literature. Further studies are needed to fully characterize its in vivo pharmacological profile. The compound is a research tool for studying USP7 and the p53 pathway.
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| Enzyme Assay |
Cell-free assays for (R)-FT671 involve evaluating its inhibitory activity against USP7. Enzyme activity is monitored using fluorogenic ubiquitin-AMC substrates that are cleaved by active USP7. Inhibition is assessed by incubating USP7 with varying concentrations of (R)-FT671 and measuring residual activity. IC50 values (52 nM) are determined from dose-response curves. Binding affinity (Kd = 65 nM) is determined using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). Chemical purity and identity are confirmed by HPLC and NMR analysis.
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| Cell Assay |
In vitro cellular assays for (R)-FT671 typically involve treating cancer cells with various concentrations of the compound. p53 and MDM2 levels are measured by western blotting. p21 expression is assessed as a marker of p53 activation. Cell viability is assessed using MTT, CellTiter-Glo, or other standard assays. Apoptosis is evaluated using Annexin V/PI staining and caspase activity assays. Dose-response curves are generated to determine IC50 values. The compound is typically dissolved in DMSO and diluted in cell culture medium.
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| Animal Protocol |
In vivo animal studies for (R)-FT671 are conducted in mouse xenograft models of cancer. The compound is administered via various routes including oral gavage or intraperitoneal injection. Tumor growth is monitored by measuring tumor volume using calipers. p53, MDM2, and p21 levels in tumor tissues are assessed by western blotting and immunohistochemistry. Pharmacodynamic endpoints include assessment of USP7 inhibition and p53 pathway activation. Efficacy is evaluated by comparing tumor growth between treatment and control groups.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of (R)-FT671 include a molecular weight of 533.48 g/mol and molecular formula C24H23F4N7O3. As a small molecule inhibitor, it is expected to have moderate oral bioavailability and tissue penetration. The compound is typically stored at appropriate conditions as a research reagent. Detailed ADME parameters such as half-life, Cmax, and AUC are not extensively reported in the available literature.
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| Toxicity/Toxicokinetics |
The toxicity profile of (R)-FT671 has been characterized in preclinical studies. As a USP7 inhibitor that activates the p53 pathway, potential toxicities may include effects on normal cell cycle regulation and apoptosis. Standard toxicology studies would include acute and sub-chronic toxicity assessments in rodent models. The compound is intended for research use only and not for therapeutic applications in humans. Standard safety precautions should be followed when handling this compound.
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| References |
[1]. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature. 2017 Oct 26;550(7677):481-486.
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| Additional Infomation |
(R)-FT671 is the R-isomer of FT671, a potent, non-covalent, and selective USP7 inhibitor with an IC50 of 52 nM and a Kd of 65 nM. By inhibiting USP7, it destabilizes MDM2, increases p53 levels, induces p21, and inhibits tumor growth. (R)-FT671 is a research tool for studying USP7, the p53 pathway, and cancer biology. It has not entered clinical trials and is strictly for research purposes.
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| Molecular Formula |
C24H23F4N7O3
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|---|---|
| Molecular Weight |
533.478138208389
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| Exact Mass |
533.179
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| CAS # |
1959551-27-9
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| Related CAS # |
1959551-27-9 (R-isomer); 1959551-26-8
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| PubChem CID |
121457109
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
38
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| Complexity |
898
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN(CCC1(CN2C=NC3=C(C2=O)C=NN3C4=CC=C(C=C4)F)O)C(=O)C[C@H](C(F)F)N5C=CC(=N5)F
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| InChi Key |
BLSNYSFLZAWBIV-GOSISDBHSA-N
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| InChi Code |
InChI=1S/C24H23F4N7O3/c25-15-1-3-16(4-2-15)35-22-17(12-30-35)23(37)33(14-29-22)13-24(38)6-9-32(10-7-24)20(36)11-18(21(27)28)34-8-5-19(26)31-34/h1-5,8,12,14,18,21,38H,6-7,9-11,13H2/t18-/m1/s1
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| Chemical Name |
5-[[1-[(3R)-4,4-difluoro-3-(3-fluoropyrazol-1-yl)butanoyl]-4-hydroxypiperidin-4-yl]methyl]-1-(4-fluorophenyl)pyrazolo[3,4-d]pyrimidin-4-one
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| Synonyms |
FT671; FT 671; FT-671
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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 | 1.8745 mL | 9.3724 mL | 18.7448 mL | |
| 5 mM | 0.3749 mL | 1.8745 mL | 3.7490 mL | |
| 10 mM | 0.1874 mL | 0.9372 mL | 1.8745 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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