GW779439X, a pyrazolopyridine compound, is an inhibitor (blocker/antagonist) of Staphylococcus aureus PASTKinase Stk1. GW779439X enhances the effectiveness of β-lactam antibiotics against a variety of MRSA and MSSA isolates, and some even cross the breakpoint from resistance to sensitivity. GW779439X is an AURKA inhibitor that causes apoptosis through caspases 3/7.

Physicochemical Properties

Molecular Formula	C22H21F3N8
Molecular Weight	454.450953245163
Exact Mass	454.184
CAS #	551919-98-3
PubChem CID	10173796
Appearance	White to light brown solid powder
Density	1.5±0.1 g/cm3
Index of Refraction	1.680
LogP	4.03
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	4
Heavy Atom Count	33
Complexity	644
Defined Atom Stereocenter Count	0
InChi Key	ZOTNSCLLJKXGSD-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H21F3N8/c1-31-9-11-32(12-10-31)20-5-4-15(13-17(20)22(23,24)25)29-21-26-8-6-18(30-21)16-14-28-33-19(16)3-2-7-27-33/h2-8,13-14H,9-12H2,1H3,(H,26,29,30)
Chemical Name	N-[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro

Biochemical factor Stk1 (GW779439X, 2 μM). Ceftaroline's efficacy against MRSA strains resistant to ceftaroline is boosted by GW779439X (5 μM). Oxacillin's efficacy against a range of isolates of Staphylococcus aureus, including MRSA and MSSA isolates, is boosted by GW779439X. GW779439X inhibits the growth of the AGP-01 cell line (IC50 = 0.57 μM). PBP2A-containing solutions exhibit the strongest enhancement effect of GW779439X (1 μM), which significantly fluctuates the G0/G1 phase and sub-G1 [1]. Genes associated with proliferation progression (c-MYC, NRAS, and CDC25A) exhibit significantly lower expression levels when exposed to 1 μM of GW779439X for 72 hours in AGP-01 cells. Conversely, genes associated with cell cycle arrest (TP53 and CDKN1A) exhibit significantly higher expression levels [2].

References

[1]. Kinase inhibitor screening reveals aurora-a kinase is a potential therapeutic and prognostic biomarker of gastric cancer [published online ahead of print, 2021 Jun 23]. J Cell Biochem. 2021;10.1002/jcb.30015. [2]. GW779439X and Its Pyrazolopyridazine Derivatives Inhibit the Serine/Threonine Kinase Stk1 and Act As Antibiotic Adjuvants against β-Lactam-Resistant Staphylococcus aureus. ACS Infect Dis. 2018;4(10):1508-1518.

Solubility Data

Solubility (In Vitro)

DMSO : ~31.25 mg/mL (~68.76 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2005 mL	11.0023 mL	22.0046 mL
	5 mM	0.4401 mL	2.2005 mL	4.4009 mL
	10 mM	0.2200 mL	1.1002 mL	2.2005 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.