Pimasertib (AS-703026)

Catalog No.S1475 Synonyms: MSC1936369B, SAR 245509

For research use only.

Pimasertib (AS-703026, MSC1936369B, SAR 245509) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.

Pimasertib (AS-703026) Chemical Structure

CAS No. 1236699-92-5

Selleck's Pimasertib (AS-703026) has been cited by 37 publications

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Biological Activity

Description Pimasertib (AS-703026, MSC1936369B, SAR 245509) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 of 5 nM-2 μM in MM cell lines. Phase 2.
Features A novel, highly selective and potent allosteric inhibitor of MEK1/2.
Targets
MEK1/2 (MM cell line) [1]
(Cell-free assay)
5 nM-2 μM
In vitro

AS703026 is a novel, selective, orally bioavailable MEK1/2 inhibitor that binds to the distinctive MEK allosteric site and therefore exhibits exquisite kinase selectivity. AS703026 inhibits growth and survival of human multiple myeloma (MM) cells, including U266 and INA-6, with IC50 of 5 nM and 11 nM, respectively. Such an inhibitory effect by AS703026 is mediated by G0-G1 cell cycle arrest and is accompanied by reduced expresson of the MAF oncogene. AS703026 further induces apoptosis via caspase-3 and PARP cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). [1] AS703026 may be an effective therapy in colorectal cancer caused by K-Ras mutation. AS703026 (10 μM) effectively inhibits the ERK pathway, proliferation, and transformation in human DLD-1 colorectal cancer cells what carry a mutant allele of K-Ras (D-MUT). [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
human COLO205 cells MY\GeY5kfGmxbjDhd5NigQ>? NIr5W5VKdmirYnn0bY9vKG:oIF3FT|EhcW5iaIXtZY4hS0:OT{KwOUBk\WyuczygTWM2OD1yLkCwNVgyKM7:TR?= MlW5NlQ4PTV2Mk[=
Assay
Methods Test Index PMID
Western blot p-ERK / ERK 27102436
Growth inhibition assay Cell viability 26381508
In vivo AS703026 (15 and 30 mg/kg) significantly inhibits tumor growth in a human plasmacytoma xenograft model of H929 MM cells. This can be correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels. [1] AS703026 (10 mg/kg) inhibits tumor growth, and markedly decreases p-ERK level in a xenograft mouse model of human K-Ras mutated (D-MUT) colorectal tumor. [2]

Protocol (from reference)

Kinase Assay:[3]
  • MEK1 enzyme assays:

    AS703026 is dissolved in 2.5% DMSO. Activated diphosphorylated MEK (pp-MEK) assays contained 40 μM 33P-γATP (AppKm 8.5 μM), 0.5 nM human-activated MEK1 or MEK2, 1 μM kinase-dead ERK2 (AppKm 0.73 μM). All assays are done in buffer containing 20 mM HEPES (pH 7.2), 5 mM 2-mercaptoethanol, 0.15 mg/mL BSA, and 10 mM MgCl2. The final concentration of 33P- ATP is 0.02 μCi/μL for all the assays. pp-MEK kinase reactions are stopped after 40 min by transferring 30 μL of reaction mixture to Durapore 0.45-μm filters plates containing 12.5% TCA. Filters are dried and read with liquid scintilant on a TopCount. Concentration response data are analyzed for IC50. 0.2 nM recombinant human MEK1 or MEK2 is preincubated with vehicle or with AS703026 for 40 minutes in reaction buffer to determine IC50 of initially unphosphorylated MEK (u-MEK). Phosphorylation/activation is initiated by the addition of a final concentration of 20 nM final B-RafV600E and 30 μM final ATP for 10 min. B-Raf activity is then quenched by addition of the B-Raf inhibitor SB590885 (final concentration 100 nM), and MEK kinase activity is assayed by the addition of 1 μM KD-ERK2 and 0.02 μCi/μL 33P-ATP in reaction buffer. The kinase reactions are stopped after 90 min by transferring 30μL of reaction mixture to a Durapore filter plate, and read as above.

Cell Research:[1]
  • Cell lines: U266 and INA-6 cells
  • Concentrations: 2 nM - 20 μM (stock: 10 mM in DMSO)
  • Incubation Time: 48 hours
  • Method: Cytotoxicity assays for AS703026 are assessed by measuring both [3H]thymidine incorporation and MTT dye absorbance. Cells (1 × 104 per well) are cultured in 96-well plates for 3 days. For the [3H]thymidine incorporation assay, cells are pulsed with 18.5 kBq/well [3H]thymidine for 6 hours, harvested onto glass fibre filters, and counted in a β-scintillation counter. Cell cycle analysis is assessed by propidium iodide (PI) staining using flow cytometry. AS703026-induced apoptosis is determined by annexin-V/PI staining and flow cytometric data analysis.
Animal Research:[1]
  • Animal Models: H929 MM xenografts are established in CB17 (SCID) mice
  • Dosages: 15 or 30 mg/kg
  • Administration: Oral gavage twice daily

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
0.5% CMC+0.25% Tween 80
For best results, use promptly after mixing.

30 mg/mL

Chemical Information

Molecular Weight 431.20
Formula

C15H15FIN3O3

CAS No. 1236699-92-5
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C1=CC(=C(C=C1I)F)NC2=C(C=CN=C2)C(=O)NCC(CO)O

In vivo Formulation Calculator (Clear solution)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Molarity Calculator

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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01985191 Completed Drug: SAR405838|Drug: Pimasertib Neoplasm Malignant Sanofi|Merck KGaA Darmstadt Germany November 2013 Phase 1
NCT01713036 Completed Drug: Pimasertib Locally Advanced or Metastatic Solid Tumors Merck KGaA Darmstadt Germany November 30 2012 Phase 1
NCT01668017 Terminated Drug: Pimasertib Advanced Solid Tumors|Hepatocellular Carcinoma Merck KGaA Darmstadt Germany|Merck Serono Co. Ltd. Japan September 30 2012 Phase 1
NCT01378377 Terminated Drug: Pimasertib|Drug: Temsirolimus Advanced Solid Tumor EMD Serono May 27 2011 Phase 1

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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