A1196-5mg | SGX-523 [1022150-57-7] Clinisciences

Background

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.

Product Citation

1. Shi P, Oh YT, et al. "Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment." Cancer Lett. 2016 Jul 19;380(2):494-504. PMID:27450722

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	359.41
Cas No.	1022150-57-7
Formula	C₁₈H₁₃N₇S
Solubility	≥17.95 mg/mL in DMSO
Chemical Name	6-[[6-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]quinoline
SDF	Download SDF
Canonical SMILES	CN1C=C(C=N1)C2=NN3C(=NN=C3SC4=CC5=C(C=C4)N=CC=C5)C=C2
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Kinase experiment [1]:
Kinase assay	Initial rate constants were 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) were quenched with 20 μL Kinase-Glo detection buffer. Luminescence was detected in a plate-reading luminometer and the results were analyzed by nonlinear regression.
Cell experiment [1]:
Cell lines	MDCK cells
Preparation method	The solubility of this compound in DMSO is > 18 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
Reacting condition	0.04, 0.12, 0.36 and 3.0 μM; overnight
Applications	In MDCK canine kidney epithelial cells, SGX-523 prevented HGF-induced cell scattering.
Animal experiment [1]:
Animal models	Nude mice bearing GTL16 gastric cancer cell xenografts
Dosage form	10, 20, 30, 100 mg/kg, b.i.d., or 60 mg/kg, q.d.; p.o.
Applications	At the dose of ﹥ 10 mg /kg twice daily, SGX523 significantly retarded the growth of GTL16 xenografts. In addition, SGX523 substantially inhibited MET kinase activity.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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.