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FRAX 597

Names

[ CAS No. ]:
1286739-19-2

[ Name ]:
FRAX 597

[Synonym ]:
6-[2-Chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-{[4-(4-methyl-1-piperazinyl)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride (1:1)
frax597
Pyrido[2,3-d]pyrimidin-7(8H)-one, 6-[2-chloro-4-(5-thiazolyl)phenyl]-8-ethyl-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-, hydrochloride (1:1)
6-(2-Chloro-4-thiazol-5-yl-phenyl)-8-ethyl-2-[4-(4-Methyl-piperazin-1-yl)-phenylaMino]-8H-pyrido[2,3-d]pyriMidin-7-one
FRAX 597

Biological Activity

[Description]:

FRAX597 is a potent group I p21-activated Kinases (PAKs) inhibitor with IC50 of 8, 13 and 19 nM for PAK1, 2 and 3.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> PAK
Signaling Pathways >> Cytoskeleton >> PAK
Research Areas >> Cancer

[Target]

PAK1:8 nM (IC50)

PAK2:13 nM (IC50)

PAK3:19 nM (IC50)


[In Vitro]

FRAX597 is determined to be a potent, ATP-competitive inhibitor of group I PAKs (PAK 1-3), with biochemical IC50 values as follows: PAK1 IC50=8 nM, PAK2 IC50=13 nM, PAK3 IC50=19 nM. The IC50 toward PAK4, a member of group II PAKs is >10 μM. At a concentration of 100 nM FRAX597 displays a significant (>80% inhibition) inhibitory capacity toward YES1 (87%), RET (82%), CSF1R (91%), TEK (87%), PAK1 (82%), and PAK2 (93%). When measured using the Kinase Glo Assay in the presence of 20 nM protein and 1 μM ATP, FRAX597 displayed an IC50 value of 48 nM against wild type PAK1, while IC50 values against the V342F and V342Y PAK1 mutants are higher than 3 μM and 2 μM, respectively[1].

[In Vivo]

Analysis of the flux reading for the animals in the two cohorts demonstrates a significantly slower tumor growth rate in FRAX597-treated mice compared with control mice. After 14 days of treatment the animals are sacrificed and the tumors excised and weighed. FRAX597-treated cohort shows significantly lower average tumor weight compared with the control cohort (0.55 g versus 1.87 g, p=0.0001)[1].

[Cell Assay]

30,000 SC4 cells/well are plated in 12-well dishes in triplicate. Cell growth media with or without FRAX597 (1 μM) is replaced daily. At indicated time points, cells from individual wells are trypsinized and counted using a Coulter counter. Statistical analysis is performed using a Student's t test. For cell cycle analysis, cells are harvested, washed once with PBS and fixed in cold 70% ethanol. Fixed cells are resuspended in propidium iodide (PI) buffer (50 μg/mL PI, 250 mg/mL RNase A in PBS) and incubated overnight at 4°C in the dark. Cell cycle distribution is evaluated using Coulter Epics XL flow cytometer. Data are analyzed using WinMDI software[1].

[Animal admin]

Mice[1] Nf2-/- SC4 Schwann cells are transduced by lentiviruses carrying pLuc-mCherry and sorted by FACS. 5×104 cells are transplanted into the sciatic nerve sheath of NOD/SCID mice (8 weeks of age) by intraneural injection. Tumor progression is monitored weekly by bioluminescence imaging (BLI) on an IVIS-200 system. The representative images from bioluminescence imaging (BLI) of mice carrying orthotopic tumors treated with FRAX597 (100 mg/kg) or vehicle control at day 14 of treatment. NOD/SCID mice are injected intraneurally with 5×104 SC4/pLuc-mCherry cells and are enrolled into treatment after 10 days. Mice are treated daily for 14 days and imaged every 3 days to follow tumor development.

[References]

[1]. Licciulli S, et al. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013 Oct 4;288(40):29105-14.


[Related Small Molecules]

PF-3758309 | FRAX 486 | G 5555 | IPA-3 | FRAX1036 | 5-Aminosalicylic Acid | KPT-9274 | NVS-PAK1-1 | GNE 2861

Chemical & Physical Properties

[ Molecular Formula ]:
C29H28ClN7OS

[ Molecular Weight ]:
558.10

[ PSA ]:
110.65000

[ LogP ]:
5.97750

[ Storage condition ]:
-20℃

Related Compounds