Pimasertib (AS-703026)MEK1/2 inhibitor CAS# 1236699-92-5 |
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Quality Control & MSDS
Number of papers citing our products
Chemical structure
3D structure
Cas No. | 1236699-92-5 | SDF | Download SDF |
PubChem ID | 44187362 | Appearance | Powder |
Formula | C15H15FIN3O3 | M.Wt | 431.2 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | Pimasertib; MSC1936369B | ||
Solubility | DMSO : ≥ 100 mg/mL (231.91 mM) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)pyridine-4-carboxamide | ||
SMILES | C1=CC(=C(C=C1I)F)NC2=C(C=CN=C2)C(=O)NCC(CO)O | ||
Standard InChIKey | VIUAUNHCRHHYNE-JTQLQIEISA-N | ||
Standard InChI | InChI=1S/C15H15FIN3O3/c16-12-5-9(17)1-2-13(12)20-14-7-18-4-3-11(14)15(23)19-6-10(22)8-21/h1-5,7,10,20-22H,6,8H2,(H,19,23)/t10-/m0/s1 | ||
General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. |
Description | Pimasertib (AS-703026) is a highly selective, potent, ATP non-competitive allosteric inhibitor of MEK1/2 with IC50 values of 5 nM-2 μM in human multiple myeloma (MM) cell lines. | |||||
Targets | MEK1/2 | |||||
IC50 | 5 nM-2 μM |
Pimasertib (AS-703026) Dilution Calculator
Pimasertib (AS-703026) Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.3191 mL | 11.5955 mL | 23.1911 mL | 46.3822 mL | 57.9777 mL |
5 mM | 0.4638 mL | 2.3191 mL | 4.6382 mL | 9.2764 mL | 11.5955 mL |
10 mM | 0.2319 mL | 1.1596 mL | 2.3191 mL | 4.6382 mL | 5.7978 mL |
50 mM | 0.0464 mL | 0.2319 mL | 0.4638 mL | 0.9276 mL | 1.1596 mL |
100 mM | 0.0232 mL | 0.116 mL | 0.2319 mL | 0.4638 mL | 0.5798 mL |
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. |
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IC50: ranging from 0.005 to 2 μM for the growth of MM cell lines
The MEK/ERK pathway transmits mitogenic signals to the nucleus and thus regulates the expression of genes that are critical for survival, proliferation, and differentiation. This pathway is often upregulated in cancer as result of oncogenic mutations. MEK is a crucial kinase in this pathway and has been targeted for the therapeutic agents development that block the MEK/ERK signaling cascade. AS 703026 is a novel small molecule MEK inhibitor.
In vitro: AS 703026 binds to the distinctive MEK allosteric site and therefore exhibits exquisite kinase selectivity. The AS 703026 binding to MEK is independent of ATP, and results in enzyme inhibition by prevention of activation. This inhibitor shows strong antiproliferative effect on tumor cell lines bearing oncogenic mutations or amplifications along the MEK/ERK pathway [1].
In vivo: In relevant mouse xenograft models, AS 703026 inhibits tumor growth after oral administration. The effect on tumor growth is dose-dependant and correlates with target modulation in both tumors and blood [1].
Clinical trial: 16 patients were enrolled in the trial. 10 and 6 patients were treated daily with 45 and 60 mg of AS 703026 plus FOLFIRI, respectively. The MTD was considered to be 45 mg/day. Of the 15 patients in the efficacy analysis group, 2 patients had partial response, 9 patients had stable disease, 3 patients had progressive disease as their best overall response and 1 patient could not be evaluated.
Reference:
[1] Goutopoulos A, Askew BC, Bankston D, Clark A, Dhanabal M, Dong R, Fischer D, Healey B, Jiang X, Josephson K, Lin J, Ma J, Noonan T, Qiu D, Rocha C, Romanelli A, Shutes A, Spooner E, Tian H, H Y. AS703026: a novel allosteric MEK inhibitor. AACR Annual meeting. 2009 Abstract#4776.
[2] Macarulla T, Cervantes A, Tabernero J et al. Phase I study of FOLFIRI plus pimasertib as second-line treatment for KRAS-mutated metastatic colorectal cancer. Br J Cancer. 2015 Jun 9;112(12):1874-81.
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Targeting the RAS pathway by mitogen-activated protein kinase inhibitors.[Pubmed:26691679]
Swiss Med Wkly. 2015 Dec 21;145:w14207.
Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.
Phase I single dose, two-period and two-sequence cross-over trial to evaluate the relative bioavailability of two oral pimasertib formulations in advanced cancer patients.[Pubmed:28289865]
Cancer Chemother Pharmacol. 2017 Apr;79(4):681-688.
PURPOSE: A phase I two-period two sequence cross-over study compared the bioavailability of two pimasertib (MSC1936369B/AS703026) formulations (capsule versus tablet) in advanced cancer patients. METHODS: Patients with advanced solid tumors were randomized to one of two treatment sequences utilizing pimasertib tablet (test; 3 x 20 mg, PO QD) and capsule (standard; 2 x 30 mg, PO QD). The trial comprised a screening and baseline period, two time periods or parts A and B, and a trial extension phase. RESULTS: N = 38 patients were randomized to two treatment sequences S1 and S2. PK parameters t 1/2, CL/f, and V z/f were within the same range for the two formulations. Tablet had bioavailability comparable to capsule based on the analysis of AUC0-t, however, tablet administration resulted in an increase of ~25% in C max versus capsule. Common predicted adverse events of pimasertib included ocular events, diarrhea and creatine phosphokinase elevation. Disease control rate was ~29% with 1 partial response and 4 of 10 patients with stable disease >4 months. CONCLUSIONS: Pimasertib tablet was overall well tolerated, had a similar safety and efficacy profile to standard capsule formulation and had bioavailability comparable to capsule.
Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib.[Pubmed:26924269]
J Mol Cell Cardiol. 2016 Apr;93:84-97.
Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.