SGX-523

Catalog No.S1112

SGX-523 is a selective Met inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α. Phase 1.

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SGX-523 Chemical Structure

SGX-523 Chemical Structure
Molecular Weight: 359.41

Validation & Quality Control

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Quality Control & MSDS

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description SGX-523 is a selective Met inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α. Phase 1.
Targets c-Met [1] B-Raf (V599E) [1] C-Raf [1] Abl [1]

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IC50 4 nM >7 μM >7 μM >7 μM
In vitro SGX-523 belongs to the class of c-Met/hepatocyte growth factor receptor (HGFR) tyrosine kinase inhibitors. SGX-523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for its selectivity. SGX523 potently inhibits the purified MET catalytic domain but not the closely related receptor tyrosine kinase RON. SGX523 indicates ATP-competitive inhibition with higher apparent affinity for the less active, unphosphorylated form of MET [MET-KD(0P), with a Ki of 2.7 nM] versus the more active phospho-enzyme [MET-KD(3P), with a Ki of 23 nM], a phenomenon consistent with preferential binding to an inactive enzyme conformation. SGX523 inhibits 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.[1]
In vivo SGX523 significantly retards the growth of preestablished GTL16 tumors when administered orally at doses of ≥10 mg/kg twice daily. SGX523 potently inhibits U87MG tumor growth; at 30 mg/kg dosed twice daily, SGX523 leads to clear regression of U87MG tumors. SGX523, dosed twice daily at 30 mg/kg, also retards the growth of H441 tumors with concomitant reduction in tumor MET autophosphorylation levels. SGX523 inhibition of MET in vivo is associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma, lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase assays Initial rate constants are measured at 21 °C in the presence of 100 mM HEPES (pH 7.5), 0.3 mg/mL poly(Glu-Tyr) peptide substrate, 10 mM MgCl2, 1 mg/mL bovine serum albumin, 5% DMSO, 20 nM MET-KD and various concentrations of ATP and SGX523. Total reaction volumes (20 μL) are quenched with 20 μL Kinase-Glo detection buffer. Luminescence is detected in a plate-reading luminometer and the results are analyzed by nonlinear regression.

Cell Assay: [1]

Cell lines MDCK cells
Concentrations 200 nM
Incubation Time 18 hours
Method MDCK cells are seeded at 1 × 103 per well in a 24-well plate and incubated at 37 °C in 5% CO2 for 1 week in MEM and 10% fetal bovine serum. HGF (90 ng/mL) and various concentrations of SGX523 are added and the cells are incubated for another 18 hours (37 °C, 5% CO2 humidified incubator) and visualized. A549 cells are plated in 12-well plates (6 × 104 per well) and incubated to confluence to investigate cell migration. A channel is introduced into the monolayers by scratching with a pipette tip. Various dilutions of compound are added in starve medium in the presence and absence of HGF (90 ng/mL).The wells are checked for cell migration after twenty-fou

Animal Study: [1]

Animal Models GTL16, U87, or H441 xenografts in Harlan nude mice
Formulation 0.5% MC 400 with 0.05% Tween 80
Dosages 60 mg/kg
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Buchanan SG, et al. Mol Cancer Ther, 2009, 8(12), 3181-3190.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00606879 Terminated Advanced Cancer SGX Pharmaceuticals, Inc. January 2008 Phase 1
NCT00607399 Terminated Advanced Cancer SGX Pharmaceuticals, Inc. January 2008 Phase 1

Chemical Information

Download SGX-523 SDF
Molecular Weight (MW) 359.41
Formula

C18H13N7S

CAS No. 1022150-57-7
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 2 mg/mL (5.56 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose+0.2% Tween 80 30 mg/mL
* <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.
Chemical Name 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline

Customer Product Validation(2)


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Rating
Source Biomarkers 2013 18(2), 126-35. SGX-523 purchased from Selleck
Method Human tumor xenografts
Cell Lines EBC-1 xenograft tumor
Concentrations 10, 3, 0.1 mg/kg
Incubation Time 8 h
Results To identify whether c-Met activation would affect c-Met shedding rate, it treated EBC-1 xenograft mice with a selective c-Met inhibitor SGX523 bid (8 h, 12 h point, respectively), and measured the phosphorylation level of c-Met and the concentration of s-Met at 24 h point. Result showed that SGX-523 potently inhibited c-Met phosphorylation in a dose-dependent manner but did not affect s-Met in plasma.

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Rating
Source Dr. Zhang of Tianjin Medical University. SGX-523 purchased from Selleck
Method Western blot
Cell Lines Breast cancer cells
Concentrations 0-1000 nM
Incubation Time 3 h
Results SGX-523 treatment resulted in a reduction of c-Met phosphorylation in Breast cancer cells.

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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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