FRAX597

PAK inhibitor,potent and ATP-competitive CAS# 1286739-19-2

FRAX597

Catalog No. BCC4172----Order now to get a substantial discount!

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Quality Control of FRAX597

Number of papers citing our products

Chemical structure

FRAX597

3D structure

Chemical Properties of FRAX597

Cas No. 1286739-19-2 SDF Download SDF
PubChem ID 70934541 Appearance Powder
Formula C29H28ClN7OS M.Wt 558.1
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 14.29 mg/mL (25.60 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one
SMILES CCN1C2=NC(=NC=C2C=C(C1=O)C3=C(C=C(C=C3)C4=CN=CS4)Cl)NC5=CC=C(C=C5)N6CCN(CC6)C
Standard InChIKey DHUJCQOUWQMVCG-UHFFFAOYSA-N
Standard InChI InChI=1S/C29H28ClN7OS/c1-3-37-27-20(14-24(28(37)38)23-9-4-19(15-25(23)30)26-17-31-18-39-26)16-32-29(34-27)33-21-5-7-22(8-6-21)36-12-10-35(2)11-13-36/h4-9,14-18H,3,10-13H2,1-2H3,(H,32,33,34)
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 FRAX597

DescriptionFRAX597 is a potent and ATP-competitive inhibitor of group I p21-activated kinases (PAKs) with IC50 values of 8 nM, 13 nM and 19 nM for PAK1, PAK2 and PAK3, respectively.
TargetsPAK1PAK2PAK3   
IC508 nM13 nM19 nM    

Protocol

Cell experiment [1]:

Cell lines

Nf2-null SC4 Schwann cells

Preparation method

Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

96 h

Applications

FRAX597 treatment significantly inhibits cellular proliferation. FRAX597-treated cells are increased in G1phase (74% versus 50% in control-treated cells) and decreased in the fraction of cells in S phase (12% versus 27% in control) and G2/M phase (11% versus 22% in control).

Animal experiment [1]:

Animal models

NOD/SCID mice (8 weeks of age), transplanted with Nf2-/- SC4 Schwann cells into the sciatic nerve sheath.

Dosage form

100 mg/kg; oral; once daily for 14 days.

Application

FRAX597-treatment significantly slows tumor growth rate in mice compared to control mice. Moreover, FRAX597-treated cohort exhibits prominently lower average tumor weight compared to the control cohort.

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. Licciulli S, Maksimoska J, Zhou C 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.

FRAX597 Dilution Calculator

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FRAX597 Molarity Calculator

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Preparing Stock Solutions of FRAX597

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7918 mL 8.959 mL 17.9179 mL 35.8359 mL 44.7948 mL
5 mM 0.3584 mL 1.7918 mL 3.5836 mL 7.1672 mL 8.959 mL
10 mM 0.1792 mL 0.8959 mL 1.7918 mL 3.5836 mL 4.4795 mL
50 mM 0.0358 mL 0.1792 mL 0.3584 mL 0.7167 mL 0.8959 mL
100 mM 0.0179 mL 0.0896 mL 0.1792 mL 0.3584 mL 0.4479 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 FRAX597

FRAX597 is a small-molecule inhibitor of the group 1 p21-activated kinases (PAKs) with IC50 values of 8nM, 13nM and 19nM, respectively for PAK1, PAK2 and PAK3 [1].

The PAKs family includes two sub groups: 1 and 2. These kinases take participate in the growth of various types of cancers. FRAX597 is developed to be an inhibitor of group 1 PAKs from the initial hits of a high throughput screen. It is an ATP-competitive inhibitor of PAK 1-3. To group 2 PAKs, FRAX597 shows minimal inhibitory activity. The inhibition mechanism of FRAX597 is that it binds PAK by targeting the ATP binding site and competes with ATP. FRAX597 is reported to suppress cell proliferation by arresting cell cycle in G1 without impacting cell viability in Schwann cells. In vivo assay also demonstrates FRAX597 can suppress tumor growth in an orthotopic model of NF2. This effect on the cells has been proved to be mediated through the inhibition of the group I PAKs [1].

References:
[1] Silvia Licciulli, Jasna Maksimoska, Chun Zhou, Scott Troutman, Smitha Kota, Qin Liu, Sergio Duron, David Campbell, Jonathan Chernoff, Jeffery Field, Ronen Marmorstein and Joseph L. Kissil. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits schwannomas tumorigenesis of NF2-associated. J. Biol. Chem. 2013, August.

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References on FRAX597

FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine.[Pubmed:26774265]

BMC Cancer. 2016 Jan 16;16:24.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. METHODS: PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. RESULTS: PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1alpha expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo. CONCLUSIONS: These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment.

FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas.[Pubmed:23960073]

J Biol Chem. 2013 Oct 4;288(40):29105-14.

The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.

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.

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