G-5555High affinity group 1 PAK inhibitor CAS# 1648863-90-4 |
Quality Control & MSDS
3D structure
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| Cas No. | 1648863-90-4 | SDF | Download SDF |
| PubChem ID | 91664373 | Appearance | White solid |
| Formula | C25H25ClN6O3 | M.Wt | 492.96 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | CHEMBL3770443,SCHEMBL16421423 | ||
| Solubility | DMSO : ≥ 27 mg/mL (54.77 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one | ||
| SMILES | CC1=CC=CC(=N1)C2=CC(=C(C=C2)C3=CC4=CN=C(N=C4N(C3=O)CC5OCC(CO5)N)NC)Cl | ||
| Standard InChIKey | ZBCMHWUFWQFPLV-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C25H25ClN6O3/c1-14-4-3-5-21(30-14)15-6-7-18(20(26)9-15)19-8-16-10-29-25(28-2)31-23(16)32(24(19)33)11-22-34-12-17(27)13-35-22/h3-10,17,22H,11-13,27H2,1-2H3,(H,28,29,31) | ||
| 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. |
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| 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. |
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| 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. | ||
| Description | High affinity group 1 PAK (pan-PAK1, 2 and 3) inhibitor (Ki = 3.7 nM; pMEK IC50 = 69 nM). Of 235 kinases tested, other than PAK1, eight (PAK2, PAK3, KHS1, Lck, MST3, MST4, SIK2, and YSK1) were inhibited >70%. Exhibits low hERG channel activity (<50% inhibition at 10 μM). Orally bioavailable. |
G-5555 Dilution Calculator
G-5555 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.0286 mL | 10.1428 mL | 20.2856 mL | 40.5712 mL | 50.7141 mL |
| 5 mM | 0.4057 mL | 2.0286 mL | 4.0571 mL | 8.1142 mL | 10.1428 mL |
| 10 mM | 0.2029 mL | 1.0143 mL | 2.0286 mL | 4.0571 mL | 5.0714 mL |
| 50 mM | 0.0406 mL | 0.2029 mL | 0.4057 mL | 0.8114 mL | 1.0143 mL |
| 100 mM | 0.0203 mL | 0.1014 mL | 0.2029 mL | 0.4057 mL | 0.5071 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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G-5555 is a potent p21-activated kinase 1 (PAK1) inhibitor with Kis of 3.7 nM and 11 nM for PAK1 and PAK2, respectively.
In Vitro:G-5555 is a potent PAK1 inhibitor with a Ki of 3.7 nM. G-5555 shows excellent kinase selectivity and inhibits only eight out of the 235 kinases tested other than PAK1 with inhibition >70%: PAK2, PAK3, KHS1, Lck, MST3, MST4, SIK2, and YSK1. The IC50s of G-5555 against SIK2, PAK2, KHS1, MST4, YSK1, MST3 and Lck are 9, 11, 10, 20, 34, 43, 52 nM, respectively. In general, G-5555 demonstrates high selectivity for the group I PAKs. There is negligible activity for G-5555 against the hERG channel with IC50 more than 10 μM in a patch clamp assay[1]. G-5555 potently inhibits PAK2, with a Ki of 11 nM. In an array of 23 breast cancer cell lines, G-5555 has significantly greater growth inhibitory activity in cell lines that are PAK-amplified compared to non-amplified lines[2].
In Vivo:G-5555 exhibits low blood clearance and an acceptable half-life. Good oral exposure (AUC = 30 μM•h) and high oral bioavailability (F = 80%) are achieved[1]. In an H292 non-small cell lunger cancer (NSCLC) xenograft study in mice, G-5555 inhibits phosphorylation of the PAK1/2 downstream substrate mitogen-activated protein kinase 1 (MEK1) S298 and, when administered at an oral dose of 25 mg/kg b.i.d., imparts 60% tumor growth inhibition in this model13 and a PAK1 amplified breast cancer xenograft model, MDAMB-175[2].
References:
[1]. Ndubaku CO, et al. Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety. ACS Med Chem Lett. 2015 Oct 31;6(12):1241-6.
[2]. Rudolph J, et al. Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window. J Med Chem. 2016 Jun 9;59(11):5520-41.
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Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.[Pubmed:26713112]
ACS Med Chem Lett. 2015 Oct 31;6(12):1241-6.
Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.
