PF-3758309 (PF3758309) HCl is a novel, ATP-competitive and potent inhibitor of PAK4 with anticancer activity. It inhibits PAK4 with a Kd of 2.7 nM and Ki of 18.7 nM.
Physicochemical Properties
| Molecular Formula | C₂₅H₃₁CLN₈OS |
| Molecular Weight | 527.08 |
| Exact Mass | 483.214 |
| CAS # | 1279034-84-2 |
| Related CAS # | PF-3758309;898044-15-0;PF-3758309 dihydrochloride |
| PubChem CID | 76972060 |
| Appearance | Typically exists as solid at room temperature |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 36 |
| Complexity | 747 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CC1=NC2=C(SC=C2)C(N=C3C4=C(NN3)C(C)(N(C(N[C@@H](C5=CC=CC=C5)CN(C)C)=O)C4)C)=N1.Cl |
| InChi Key | DZSGSCZKFHGJNK-FSRHSHDFSA-N |
| InChi Code | InChI=1S/C25H30N8OS.ClH/c1-15-26-18-11-12-35-20(18)23(27-15)29-22-17-13-33(25(2,3)21(17)30-31-22)24(34)28-19(14-32(4)5)16-9-7-6-8-10-16;/h6-12,19H,13-14H2,1-5H3,(H,28,34)(H2,26,27,29,30,31);1H/t19-;/m1./s1 |
| Chemical Name | N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide;hydrochloride |
| Synonyms | PF3758309 HCl PF 3758309 HCl |
| 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 | PF-3758309 hydrochloride possesses comparable enzymatic activity against group A PAK1 (Ki=13.7 nM) and other group B PAKs (PAK5, Ki=18.1 nM; PAK6, Ki=17.1 nM), but it specifically targets the other two Group A PAKs (PAK2, IC50=190 nM; PAK3, IC50=99 nM) [1]. A panel of tumor cell lines' anchorage-dependent proliferation (IC50=4.7 nM) and the phosphorylation of the PAK4 substrate GEF-H1 (IC50=1.3 nM) in cells are both inhibited by PF-3758309 hydrochloride [1]. In HCT116 cells, PF-3758309 hydrochloride also prevents the build-up of endogenous pGEF-H1. A549 cells' anchorage-dependent growth (IC50=27 nM) and cell proliferation (IC50=20 nM) are both successfully suppressed by PF-3758309 [1]. |
| ln Vivo | In HCT116 and A549 models, PF-3758309 hydrochloride (7.5-30 mg/kg; oral; twice daily for 9–18 days) results in statistically significant tumor growth inhibition (TGI) [1]. |
| Animal Protocol |
Animal/Disease Models: Female nu/nu, CRL strain 6-8 weeks old mice (carrying HCT116 and A549 tumors) [1] Doses: 7.5-30 mg/kg Route of Administration: Oral; administration twice (two times) daily for 9 -18 day Experimental Results: Significant tumor growth inhibition (TGI) in HCT116 and A549 models. |
| References |
[1]. Small-molecule p21-activated kinase inhibitor PF3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proceedings of the National Academy of Sciences of the United States of America (2010), 107(20), 9446-9451, S94. [2]. Do PAKs make good drug targets? F1000 Biol Rep. 2010 Sep 23;2:70. [3]. PF-3758309, p21-activated kinase 4 inhibitor, suppresses migration and invasion of A549 human lung cancer cells via regulation of CREB, NF-κB, and β-catenin signalings. Mol Cell Biochem. 2014 Apr;389(1-2):69-77. |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8972 mL | 9.4862 mL | 18.9725 mL | |
| 5 mM | 0.3794 mL | 1.8972 mL | 3.7945 mL | |
| 10 mM | 0.1897 mL | 0.9486 mL | 1.8972 mL |