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Talmapimod, formerly known as SCIO-469, is an orally bioavailable, novel mitogen-activated protein kinase (MAPK) inhibitor with potential immunomodulating, anti-inflammatory, and antineoplastic activities (IC50 = 9 nM). It exhibits at least 2000-fold selectivity over a panel of 20 other kinases, including other MAPKs, and about 10-fold selectivity over p38. Talmapimod specifically binds to and prevents phosphorylation of p38 MAPK, which may induce tumor cell apoptosis, prevent tumor cell proliferation, and prevent tumor angiogenesis. Additionally, this substance might promote proteasome inhibitor-induced apoptosis.
| Targets |
p38α (IC50 = 9 nM); p38β (IC50 = 90 nM)
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|---|---|
| ln Vitro |
Talmapimod (SCIO-469) inhibits p38 MAPK phosphorylation in MM cells at concentrations of 100–200 nM for an hour[1].
Talmapimod reduces the amount of TNF-a that LPS causes to be produced in human whole blood[2]. Talmapimod decreases the 5T2MM and 5T33MM cells' constitutive phosphorylation of p38alpha MAPK[3]. |
| ln Vivo |
Talmapimod (SCIO-469) reduces the burden of myeloma while also preventing the emergence of myeloma bone disease[2].
Talmapimod suppresses multiple myeloma cell proliferation and guards against bone disease in the 5T2MM and 5T33MM models[3]. Talmapimod (10-90 mg/kg; p.o. ; twice daily orally for 14 days) decreased tumor weight at termination as well as tumor growth in a dose-dependent manner[4]. |
| Cell Assay |
Talmapimod (SCIO-469) was pretreated with 5TMM cells (0.5 × 106/mL) in serum-free medium before being added to the lower compartment of a Transwell system. In the Transwell itself, stromal cells from synthetic bone marrow were seeded. According to the manufacturer's instructions, the 5TMM cells were taken from the lower compartment after 18 hours and stained for active caspase-3 using a FITC-labeled antibody.
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| Animal Protocol |
Six-week-old male triple immune-deficient BNX mice (RPMI-8226 MM palpable tumors)[4]
P.o.; twice daily orally for 14 days 10, 30, 90 mg/kg |
| References |
|
| Molecular Formula |
C27H30N4O3FCL
|
|---|---|
| Molecular Weight |
513.0035
|
| Exact Mass |
512.20
|
| Elemental Analysis |
C, 63.21; H, 5.89; Cl, 6.91; F, 3.70; N, 10.92; O, 9.36
|
| CAS # |
309913-83-5
|
| Related CAS # |
Talmapimod hydrochloride;309915-12-6
|
| Appearance |
white solid powder
|
| SMILES |
C[C@@H]1CN([C@H](CN1C(=O)C2=C(C=C3C(=C2)C(=CN3C)C(=O)C(=O)N(C)C)Cl)C)CC4=CC=C(C=C4)F
|
| InChi Key |
ZMELOYOKMZBMRB-DLBZAZTESA-N
|
| InChi Code |
InChI=1S/C27H30ClFN4O3/c1-16-13-33(17(2)12-32(16)14-18-6-8-19(29)9-7-18)26(35)21-10-20-22(25(34)27(36)30(3)4)15-31(5)24(20)11-23(21)28/h6-11,15-17H,12-14H2,1-5H3/t16-,17+/m0/s1
|
| Chemical Name |
2-[6-chloro-5-[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethylpiperazine-1-carbonyl]-1-methylindol-3-yl]-N,N-dimethyl-2-oxoacetamide
|
| Synonyms |
Talmapimod; SD282; SD 282; SD-282; SCI O282; SCI-O282; SCIO282
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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: ≥ 100 mg/mL (~194.9 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.87 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.87 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 (4.87 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 | 1.9493 mL | 9.7466 mL | 19.4932 mL | |
| 5 mM | 0.3899 mL | 1.9493 mL | 3.8986 mL | |
| 10 mM | 0.1949 mL | 0.9747 mL | 1.9493 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00043732 | Completed | Drug: SCIO-469 | Rheumatoid Arthritis | Scios, Inc. | Phase 2 | |
| NCT00095680 | Completed | Drug: SCIO-469 and bortezomib Drug: SCIO-469 |
Multiple Myeloma | Scios, Inc. | November 2004 | Phase 2 |
| NCT00087867 | Completed | Drug: SCIO-469 and bortezomib Drug: SCIO-469 |
Multiple Myeloma | Scios, Inc. | June 2004 | Phase 2 |
| NCT00113893 | Completed | Drug: SCIO-469 | Bone Marrow Diseases Hematologic Diseases |
Scios, Inc. | May 2005 | Phase 2 |
| NCT00089921 | Completed | Drug: SCIO-469 Drug: Placebo |
Arthritis, Rheumatoid | Scios, Inc. | July 2004 | Phase 2 |
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