| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| Other Sizes |
Purity: ≥98%
OSI754 (also known as CP-609754, CP-609,754, LNK-754) is a novel and potent farnesyltransferase inhibitor (TFI) that has potential anticancer activity. Since farnesyltransferase is known to prevent proper functioning of Ras, a family of proteins often abnormally activated in cancer, FTIs were first developed as potential anticancer agents. A number of FTIs underwent preclinical testing but were found to have major side effects, while others entered clinical development in a variety of cancers, only to be discontinued at phase I due to a lack of efficacy.
| Targets |
Reversible farnesyl growth enzyme kinase with a slow on/off rate is CP-609754 (CP-609,754). The analysis of compounds tagged with [35S]methionine using SDS-PAGE [1] indicates that CP-609754 is competitive for the isoprene receptor (H-Ras protein), but not for the isoprene donor farnesyl PPI. When it comes to binding to Ras protein, CP-609754 reacts to and competes with the farnesyltransferase-farnesylPPI complex. In 3T3 transfectants, CP-609754 specifically prevents the farnesylation of H- and K-Ras proteins [1].
|
|---|---|
| ln Vitro |
Reversible farnesyl growth enzyme kinase with a slow on/off rate is CP-609754 (CP-609,754). The analysis of compounds tagged with [35S]methionine using SDS-PAGE [1] indicates that CP-609754 is competitive for the isoprene receptor (H-Ras protein), but not for the isoprene donor farnesyl PPI. When it comes to binding to Ras protein, CP-609754 reacts to and competes with the farnesyltransferase-farnesylPPI complex. In 3T3 transfectants, CP-609754 specifically prevents the farnesylation of H- and K-Ras proteins [1].
In 3T3 H-ras (61L)-transfected cell lines, CP-609,754 inhibits farnesylation of mutant H-Ras with an IC50 of 1.72 ng/mL, as determined by SDS-PAGE analysis of [³⁵S]methionine-labeled material. This inhibitory effect was not observed in K-Ras transfected cell lines at concentrations up to 4790 ng/mL, likely because K-Ras can be alternatively prenylated by GGTase-I in the presence of farnesyltransferase inhibitors. Analysis using tritiated prenyl precursors confirmed that CP-609,754 selectively inhibits farnesylation of both H- and K-Ras proteins in 3T3 transfectants. |
| ln Vivo |
In vivo activity of CP-609754 (CP-609,754) against 3T3 H-ras (61L) cancers has been reported [1]. Tumor suppression was achieved by continuous intraperitoneal infusion of CP-609754; tumor growth inhibition was >50%, tumor farnesyl transcriptase activity was inhibited >30%, and CP-609754 tumor growth concentration remains above 118 ng/mL. Tumor regression reached a dose of 100 mg/kg when CP-609754 was applied twice a day to the side wall [1].
In mice bearing 3T3 H-ras (61L) tumors, oral administration of CP-609,754 at 100 mg/kg twice daily resulted in tumor regression. The ED₅₀ for tumor growth inhibition was 28 mg/kg. Continuous intraperitoneal infusion of CP-609,754 inhibited tumor growth by >50% and inhibited tumor farnesyltransferase activity by >30% in mice when plasma concentrations were maintained above 118 ng/mL. [1] |
| Enzyme Assay |
The inhibitory activity of CP-609,754 against recombinant human farnesyltransferase was determined using H-Ras and K-Ras proteins as substrates, measuring the transfer of the farnesyl group. IC50 values were calculated from these assays.
Inhibition of recombinant human GGTase I activity was also assessed using CAAX-mutant forms of H-Ras and K-Ras proteins. Kinetic studies indicated that CP-609,754 is a reversible inhibitor competitive for the Ras protein acceptor and non-competitive for the farnesyl pyrophosphate donor, suggesting interaction with the farnesyltransferase-farnesyl pyrophosphate complex. |
| Cell Assay |
Inhibition of farnesylation in intact cells was assessed using 3T3 cells transfected with mutant H-ras (61L). Cells were treated with CP-609,754, metabolically labeled with [³⁵S]methionine, and then lysed. Proteins were separated by SDS-PAGE, and the farnesylation status of Ras was analyzed.
An alternative assay used tritiated prenyl precursors instead of [³⁵S]methionine to specifically track protein prenylation in the transfected cells. |
| Animal Protocol |
For in vivo antitumor activity, mice bearing 3T3 H-ras (61L) tumors were treated with CP-609,754 administered orally at 100 mg/kg twice daily. Tumor volume was monitored to assess regression and calculate the ED₅₀ for growth inhibition.
For pharmacodynamic analysis, mice received continuous intraperitoneal infusion of CP-609,754 to maintain steady plasma concentrations. Tumor growth and tumor farnesyltransferase activity were measured. |
| ADME/Pharmacokinetics |
In a Phase I clinical trial, CP-609,754 was administered orally in tablet form to patients with advanced solid tumors. Pharmacokinetic parameters were derived from plasma concentration-time data. The half-life (T₁/₂) was approximately 3 hours. At a dose of 640 mg twice daily, the mean maximum plasma concentration (Cmax) was 1250 ng/mL (dose administered on the morning of day 1) and 1110 ng/mL (dose administered on the morning of day 15), respectively. Maximum concentration (Tmax) was reached 1–2 hours after morning administration. The mean area under the curve (AUC₀-τ) over the dosing interval on day 15 was 3650 ng/mL for morning administration and 3480 ng/mL for evening administration. The plasma concentration (Cmin) observed at the end of the dosing interval on day 15 was 46 ng/mL for morning administration and 101 ng/mL for evening administration.
Drug accumulation after multiple doses was lower than expected, with average accumulation ratios of 0.75 (morning dose) and 0.54 (evening dose), respectively. Drug exposure increased proportionally to dose, and oral absorption was rapid. |
| Toxicity/Toxicokinetics |
In the Phase I trial, the dose-limiting toxicity (DLT) was Grade 3 neuropathy (dizziness and gait instability), which occurred in 1 of 6 patients treated with 640 mg twice daily. Other treatment-related Grade 3/4 adverse events included: lymphopenia (common in all dose groups), anemia, leukopenia (including one case of febrile neutropenia in the 640 mg twice daily dose group), thrombocytopenia, hypokalemia, fatigue, pain, and confusion. One patient taking warfarin experienced coagulation dysfunction with prolonged prothrombin time, suggesting a possible drug interaction. Grade 3 elevations in gamma-glutamyl transferase and serum creatinine were observed in some patients, but in one patient, the elevated serum creatinine was attributed to disease progression. No treatment-related deaths occurred. Common adverse events in the 640 mg twice-daily dose group included neuropathy, fatigue, pain, diarrhea, nausea, and vomiting (mostly grade 1-2).
|
| References | |
| Additional Infomation |
LNK 754 has been studied in mild Alzheimer's disease. CP-609,754 is a quinolinone derivative that inhibits farnesyltransferase (an enzyme mediating the farnesylation of Ras protein), potentially inhibiting the RAS pathway. CP-609,754 is also known as OSI-754 or LNK-754. Its chemical name is 6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-ethynylphenyl)-1-methyl-2(1H)-quinolinone, (2R,3R)-2,3-dihydroxysuccinic acid (1:1), D(-)tartrate. It is a reversible farnesyltransferase inhibitor with a slow binding/dissociation rate. Its main mechanism is the inhibition of farnesylation of Ras protein, a key step in Ras protein membrane localization and oncogenic signaling. Inhibition of other farnesylated proteins (e.g., RhoB) may also contribute to its effect. Based on preclinical data, maintaining plasma concentrations above 118 ng/mL is expected to be essential for clinical efficacy in treating Ras-expressing tumors. In the Phase I study, the recommended Phase II dose (RP2D) was determined to be ≥640 mg orally twice daily. Although no objective tumor response was observed, prolonged disease stability (>2 months, maximum 367 days) was observed in 10 patients across various tumor types (e.g., colorectal cancer, renal cell carcinoma, bronchioloalveolar carcinoma).
|
| Molecular Formula |
C29H22CLN3O2
|
|
|---|---|---|
| Molecular Weight |
479.96
|
|
| Exact Mass |
479.14
|
|
| CAS # |
1190094-64-4
|
|
| Related CAS # |
(Rac)-CP-609754;439153-64-7
|
|
| PubChem CID |
46208720
|
|
| Appearance |
Off-white to yellow solid powder
|
|
| Density |
1.23±0.1 g/cm3
|
|
| Boiling Point |
702.4±60.0 °C
|
|
| LogP |
4.857
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
3
|
|
| Rotatable Bond Count |
5
|
|
| Heavy Atom Count |
35
|
|
| Complexity |
874
|
|
| Defined Atom Stereocenter Count |
1
|
|
| SMILES |
CN1C=NC=C1[C@@](C2=CC=C(C=C2)Cl)(C3=CC4=C(C=C3)N(C(=O)C=C4C5=CC=CC(=C5)C#C)C)O
|
|
| InChi Key |
JAHDAIPFBPPQHQ-GDLZYMKVSA-N
|
|
| InChi Code |
InChI=1S/C29H22ClN3O2/c1-4-19-6-5-7-20(14-19)24-16-28(34)33(3)26-13-10-22(15-25(24)26)29(35,27-17-31-18-32(27)2)21-8-11-23(30)12-9-21/h1,5-18,35H,2-3H3/t29-/m1/s1
|
|
| Chemical Name |
|
|
| Synonyms |
|
|
| HS Tariff Code |
2934.99.9001
|
|
| 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.21 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 (5.21 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0835 mL | 10.4175 mL | 20.8351 mL | |
| 5 mM | 0.4167 mL | 2.0835 mL | 4.1670 mL | |
| 10 mM | 0.2084 mL | 1.0418 mL | 2.0835 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA