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| Targets |
PAK4 (p21-activated kinase 4). PF-3758309 HCl is a potent, ATP-competitive inhibitor of PAK4 with a Kd of 2.7 nM and a Ki of 18.7 nM. PAK4 is a member of the group II PAK family of serine/threonine kinases that are activated by small GTPases of the Rho family, particularly Cdc42. PAK4 plays critical roles in cell motility, survival, proliferation, and cytoskeletal remodeling. It is frequently overexpressed or hyperactivated in various cancers, making it an attractive therapeutic target. PF-3758309 is highly selective for PAK4 over other kinases, as demonstrated in kinase panel screening.
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| 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].
PF-3758309 HCl demonstrates potent in vitro activity against PAK4 with a Kd of 2.7 nM and a Ki of 18.7 nM. In cell-based assays, the compound exhibits expected cellular functions of a PAK4 inhibitor, including inhibition of anchorage-independent growth (a hallmark of transformed cells), induction of apoptosis, cytoskeletal remodeling, and inhibition of proliferation. The compound has potential antineoplastic activity and has been evaluated in various cancer cell lines. The compound's ATP-competitive mechanism provides potent inhibition of PAK4 kinase activity. Further detailed in vitro data, including GI50 values against various cancer cell lines, are available in the primary literature. |
| 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].
PF-3758309 HCl has demonstrated in vivo efficacy in various preclinical cancer models. The compound is orally bioavailable, supporting its use in oral dosing regimens. In xenograft models, PF-3758309 administration results in dose-dependent inhibition of tumor growth, accompanied by reduced PAK4 activity and downstream signaling in tumor tissues. The compound has been evaluated in various tumor types, showing antitumor activity. Detailed in vivo data, including efficacy in various tumor types, pharmacokinetic-pharmacodynamic relationships, and combination studies, are available in the primary literature. |
| Enzyme Assay |
Kinase inhibition assays for PF-3758309 HCl are performed using recombinant PAK4 enzyme. The compound is incubated with the enzyme and ATP, and the inhibition of kinase activity is measured using a peptide substrate. Kd of 2.7 nM and Ki of 18.7 nM are determined from binding and inhibition assays, respectively. Selectivity against other kinases is assessed using broad kinase panel screening, confirming the compound's high selectivity for PAK4.
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| Cell Assay |
Cell-based assays for PF-3758309 HCl are conducted using various cancer cell lines. Cells are treated with the compound at various concentrations, and the following endpoints are assessed: PAK4 activity (by phosphorylation of downstream substrates), cell proliferation, anchorage-independent growth (soft agar assay), apoptosis (by annexin V staining or caspase activation), and cytoskeletal organization. The compound's anti-proliferative effects are evaluated by measuring IC50 values for cell growth inhibition. The specificity of the observed effects can be confirmed by using cells with PAK4 knockdown or overexpression.
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| 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. In vivo studies for PF-3758309 HCl are performed in mouse xenograft models of various cancers. The compound is typically administered orally at various doses and schedules. Pharmacodynamic endpoints include measurement of PAK4 activity in tumor tissues (by phosphorylation assays), assessment of downstream signaling, and evaluation of tumor growth inhibition. Pharmacokinetic parameters such as plasma concentration-time profiles, half-life, clearance, and bioavailability are determined from serial blood sampling. The compound's oral bioavailability supports its use in oral dosing regimens. |
| ADME/Pharmacokinetics |
PF-3758309 HCl is orally bioavailable, with favorable pharmacokinetic properties that support its use in preclinical studies. The compound is typically administered orally in preclinical studies. Detailed PK parameters, including half-life, Cmax, AUC, and bioavailability, are available from published studies. The compound's molecular weight is 527.08, which is within the typical range for oral small molecule drugs. Storage recommendations include appropriate temperature control to maintain stability.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, PF-3758309 HCl has demonstrated an acceptable safety profile at therapeutic doses. However, specific toxicity data are not detailed in the available summary. The compound is intended for research use and is not approved for clinical use. Standard laboratory safety precautions should be followed when handling the compound.
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| References | |
| Additional Infomation |
PF-3758309 HCl is a potent, orally available, and reversible ATP-competitive inhibitor of PAK4 with potential antineoplastic activity. It has been investigated in preclinical studies for the treatment of various cancers. The compound is not approved for clinical use and is supplied for research purposes only. Synonyms include PF-03758309 hydrochloride and PF-3758309 hydrochloride. The compound is available from multiple chemical suppliers.
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| Molecular Formula |
C₂₅H₃₁CLN₈OS
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| Molecular Weight |
527.08
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| Exact Mass |
483.214
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| CAS # |
1279034-84-2
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| Related CAS # |
PF-3758309;898044-15-0;PF-3758309 dihydrochloride
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| PubChem CID |
76972060
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
36
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| Complexity |
747
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| Defined Atom Stereocenter Count |
1
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| 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
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| InChi Key |
DZSGSCZKFHGJNK-FSRHSHDFSA-N
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| 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
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| 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
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| Synonyms |
PF3758309 HCl PF 3758309 HCl
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| HS Tariff Code |
2934.99.9001
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| 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)
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| 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
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| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (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 |
*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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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