Pimasertib (AS-703026)

Catalog No.S1475 Batch:S147504

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Technical Data

Formula

C15H15FIN3O3
Molecular Weight 431.20 CAS No. 1236699-92-5
Solubility (25°C)* In vitro DMSO 86 mg/mL (199.44 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

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.
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]
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]
Features A novel, highly selective and potent allosteric inhibitor of MEK1/2.

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 Assay:[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 Study:[1]
  • Animal Models

    H929 MM xenografts are established in CB17 (SCID) mice

  • Dosages

    15 or 30 mg/kg

  • Administration

    Oral gavage twice daily

Customer Product Validation

Data from [Data independently produced by FASEB J, 2014, 10.1096/fj.13-247924]

Data from [Data independently produced by Endocrinology, 2013, 154(9), 3219-27]

, , Dr. Zhang of Tianjin Medical University

Data from [Data independently produced by , , Int J Cancer, 2018, 142(2):381-391]

Selleck's Pimasertib (AS-703026) has been cited by 45 publications

Salmonella effector SopB reorganizes cytoskeletal vimentin to maintain replication vacuoles for efficient infection [ Nat Commun, 2023, 14(1):478] PubMed: 36717589
ETS1 phosphorylation at threonine 38 is associated with the cell of origin of diffuse large B cell lymphoma and sustains the growth of tumour cells [ Br J Haematol, 2023, 10.1111/bjh.19018] PubMed: 37584198
Three generations of mTOR kinase inhibitors in the activation of the apoptosis process in melanoma cells [ J Cell Commun Signal, 2023, 17(3):975-989] PubMed: 37097377
A Cell Cycle-Dependent Ferroptosis Sensitivity Switch Governed by EMP2 [ bioRxiv, 2023, 2023.07.19.549715] PubMed: 37502927
Anatomic position determines oncogenic specificity in melanoma [ Nature, 2022, 604(7905):354-361] PubMed: 35355015
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening [ Cancers (Basel), 2022, 14(6)1575] PubMed: 35326726
Mcl-1 and Bcl-xL levels predict responsiveness to dual MEK/Bcl-2 inhibition in B-cell malignancies [ Mol Oncol, 2021, 10.1002/1878-0261.13153] PubMed: 34861096
Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer [ Commun Biol, 2021, 4(1):1333] PubMed: 34824367
Tyrosine-Dependent Phenotype Switching Occurs Early in Many Primary Melanoma Cultures Limiting Their Translational Value [ Front Oncol, 2021, 11:780654] PubMed: 34869032
A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics [ Sci Rep, 2021, 11(1):9161] PubMed: 33911106

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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