SGX-523

MET inibitor, highly selective, ATP-competitive CAS# 1022150-57-7

SGX-523

Catalog No. BCC1055----Order now to get a substantial discount!

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Chemical structure

SGX-523

3D structure

Chemical Properties of SGX-523

Cas No. 1022150-57-7 SDF Download SDF
PubChem ID 24779724 Appearance Powder
Formula C18H13N7S M.Wt 359.41
Type of Compound N/A Storage Desiccate at -20°C
Synonyms SGX523,SGX 523
Solubility DMSO : ≥ 3.6 mg/mL (10.02 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 6-[[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]quinoline
SMILES CN1C=C(C=N1)C2=NN3C(=NN=C3SC4=CC5=C(C=C4)N=CC=C5)C=C2
Standard InChIKey BCZUAADEACICHN-UHFFFAOYSA-N
Standard InChI InChI=1S/C18H13N7S/c1-24-11-13(10-20-24)16-6-7-17-21-22-18(25(17)23-16)26-14-4-5-15-12(9-14)3-2-8-19-15/h2-11H,1H3
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.
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.
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.

Biological Activity of SGX-523

DescriptionPotent and selective c-MET kinase inhibitor (IC50 = 4nM). Exhibits minimal inhibition against a panel of 213 other protein kinases (at 1 μM). Suppresses growth of tumor xenografts derived from human glioblastoma, lung and gastric cancer cells.

SGX-523 Dilution Calculator

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SGX-523 Molarity Calculator

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Preparing Stock Solutions of SGX-523

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.7823 mL 13.9117 mL 27.8234 mL 55.6468 mL 69.5584 mL
5 mM 0.5565 mL 2.7823 mL 5.5647 mL 11.1294 mL 13.9117 mL
10 mM 0.2782 mL 1.3912 mL 2.7823 mL 5.5647 mL 6.9558 mL
50 mM 0.0556 mL 0.2782 mL 0.5565 mL 1.1129 mL 1.3912 mL
100 mM 0.0278 mL 0.1391 mL 0.2782 mL 0.5565 mL 0.6956 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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Background on SGX-523

SGX-523 is a novel, potent, ATP-competitive, and highly-selective Hepatocyte growth factor receptor (MET) inhibitor with IC50 value of 4 nM [1].

SGX523 inhibits MET autophosphorylation in gastric cancer cell line GTL16 and human lung carcinoma cell line A549, with IC50 of 40 nM and 12 nM, respectively [1]. Additionally, tumor regression was observed in gastic cancer cell line GTL16 and human GBM cell line U87MG derived mouse xenograft models that are treated with SGX-523 by oral gavage [1].

SGX523 has been shown to inhibit the phosphorylateion of MEK, MAPK, AKT in brain cancer cell lines including U87, U373, DAOY, as well as glioma stem cells 1228. The inhibition of MEK in brain cancer cells and stem cells led to cell proliferation, G1/S cell cycle progression, cell migration, and cell invasion [2].

References:
[1] Buchanan SG1, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF,Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K,Wasserman SR, Emtage S, Burley SK, Reich SH. SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther. 2009 Dec;8(12):3181-90.
[2] Guessous F1, Zhang Y, diPierro C, Marcinkiewicz L, Sarkaria J, Schiff D, Buchanan S, Abounader R.An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth. Anticancer Agents Med Chem. 2010 Jan;10(1):28-35.

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References on SGX-523

Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications.[Pubmed:20421447]

Drug Metab Dispos. 2010 Aug;38(8):1277-85.

An investigation was conducted to follow up on the apparent species-dependent toxicity reported for 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin e (SGX523), a mesenchymal-epithelial transition factor (c-MET) inhibitor that entered clinical development for the treatment of solid tumors. Patients treated with SGX523 exhibited compromised renal function presumably resulting from crystal deposits in renal tubules. Our independent metabo'lite profiling of SGX523 indicates that a major NADPH-independent, late-eluting metabolite [6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoli n-2(1H)-one (M11)] was generated by monkey and human liver S-9, and to a lesser extent by rat S-9, whereas M11 was absent in dog S-9 incubations. We confirmed the identity of M11 as 2-quinolinone-SGX523. Experiments with various molybdenum hydroxylase inhibitors showed that aldehyde oxidase (AO), and not xanthine oxidase, metabolized SGX523 to M11 in monkey and human liver cytosol. In addition, the oxygen incorporated into M11 was derived from water rather than atmospheric oxygen, corroborating M11 formation via AO. After oral dosing in monkeys, metabolite profiling of plasma and urine showed that SGX523 was indeed metabolized to M11 and its N-demethyl analog (M8). In urine, M11 levels were approximately 70-fold greater than that of SGX523, and the solubility of M11 in urine was only 3% of that of SGX523. In summary, SGX523 is metabolized by AO in a species-specific manner to a markedly less-soluble metabolite, M11. We propose that M11 is likely involved in the observed obstructive nephropathy reported in clinical studies. Moreover, this study illustrates the need to conduct thorough metabolic evaluations early in drug development to select the most relevant nonclinical species for toxicological evaluation.

MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth.[Pubmed:20643778]

Cancer Res. 2010 Sep 1;70(17):6880-90.

The hepatocyte growth factor (HGF)-MET pathway supports several hallmark cancer traits, and it is frequently activated in a broad spectrum of human cancers (http://www.vai.org/met/). With the development of many cancer drugs targeting this pathway, there is a need for relevant in vivo model systems for preclinical evaluation of drug efficacy. Here, we show that production of the human HGF ligand in transgenic severe combined immunodeficient mice (hHGF(tg)-SCID mice) enhances the growth of many MET-expressing human carcinoma xenografts, including those derived from lung, breast, kidney, colon, stomach, and pancreas. In this model, the MET-specific small-molecule kinase inhibitor SGX523 partially inhibits the HGF-dependent growth of lung, breast, and pancreatic tumors. However, much greater growth suppression is achieved by combinatorial inhibition with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. Together, these results validate the hHGF(tg)-SCID mouse model for in vivo determination of MET sensitivity to drug inhibition. Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated.

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.[Pubmed:19934279]

Mol Cancer Ther. 2009 Dec;8(12):3181-90.

The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.

Novel [1,2,4] Triazol [4,3-a] Pyridine Derivatives as Potential Selective c-Met Inhibitors with Improved Pharmacokinetic Properties.[Pubmed:27804848]

Anticancer Agents Med Chem. 2017;17(8):1102-1112.

AIMS: Total twenty-nine [1,2,4]triazolo[4,3-a]pyrazine derivatives were designed and synthesized. METHOD: The target compounds, especially 4aa, showed potent activity to inhibit c-Met both in an enzyme assay and a cellular assay. The comprehensive screening for the inhibition of 60 different kinases revealed that 4aa could selectively inhibit c-Met while had no effect on other kinases, indicating 4aa is an excellent c-Met selective inhibitor. RESULT: The flow cytometry studies found that 4aa had a similar behavior to the positive control SGX-523 in terms of causing the tumor cell apoptosis and blocking cell-cycle progression. More importantly, 4aa showed much better pharmacokinetic properties than SGX-523. Altogether, the findings suggested the target compounds may be potential anti-tumor drug candidates.

Description

SGX-523 is a selective Met inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α.

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