PF-3758309

Catalog No.S7094 Batch:S709404

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Technical Data

Formula

C25H30N8OS
Molecular Weight 490.62 CAS No. 898044-15-0
Solubility (25°C)* In vitro DMSO 98 mg/mL (199.74 mM)
Ethanol 98 mg/mL (199.74 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description PF-03758309 (PF-03758309) is a potent, ATP-competitive, pyrrolopyrazole inhibitor of PAK4 with Kd of 2.7 nM. PF-3758309 is antiproliferative and induces apoptosis in a HCT116 tumor model.
Targets
PAK1 [1]
(Cell-free assay)		 PAK6 [1]
(Cell-free assay)		 PAK5 [1]
(Cell-free assay)		 PAK4 [1]
(Cell-free assay)		 PAK3 [1]
(Cell-free assay)		 View More
13.7 nM(Ki) 17.1 nM(Ki) 18.1 nM(Ki) 18.7 nM(Ki) 99 nM
In vitro

PF-3758309 is a potent (Kd = 2.7 nM), ATP-competitive inhibitor of PAK4 with Ki of 18.7 nM. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC50 = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC50 = 4.7 nM). PF-3758309 also inhibits endogenous pGEF-H1 accumulation in HCT116 cells. PF-3758309 potently inhibits cellular proliferation (IC50 = 20 nM) and anchorage-independent growth (IC50 = 27 nM) of A549 cells. [1]
In vivo

PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC50 value of 0.4 nM in the most sensitive model. PF-3758309 is antiproliferative and induces apoptosis in a HCT116 tumor model. [1]
Features PF-3758309 is potent toward a broad array of tumor cell lines from different tumor types.

Protocol (from reference)

Kinase Assay:

[1]
  • Phospho-GEF-H1 Cellular Assay

    TR-293-KDG cells are constructed from HEK293 cells stably transfected with tetracycline-inducible PAK4-kinase domain (amino acids 291-591) and constitutively expressed HA-tagged GEFH1ΔDH (amino acids 210-921). TR-293-KDG cells are incubated for 3 h with PF-3758309, captured on an anti-HA antibody-coated plate, detected with an anti-phospho-S810-GEF-H1 antibody, and quantified with a horseradish peroxidase-goat anti-rabbit antibody conjugate.
Cell Assay:

[1]
  • Cell lines

    HEK293T, HCT116, and SKOV3 cells

  • Concentrations

    ~1 μM

  • Incubation Time

    72 hours

  • Method

    A panel of cancer cell lines is used to test the potency of PF-3758309. On day 1, cells are plated on 384-well plates. Onday2, compounds are added to the cell culture. The cells are incubated with the compound for 3 days. On day 5, all media are aspirated from the wells. Dose-dependent effects of PF-3758309 on cell proliferation are quantified via the CellTiter-Glo Luminescent Cell Viability Assay(a,b,c), which is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells. Proliferation data displayed for HEK293T, HCT116, and SKOV3 cells are measured using the Cyquant NF assay as specified by the manufacturer. Results for each drug are normalized to vehicle control and expressed as a percentage of maximum assay inhibition relative to Bleomycin. Error bars represent the SD from at least three experiments.
Animal Study:

[1]
  • Animal Models

    Xenograft tumors in nude mice

  • Dosages

    7.5-30 mg/kg BID

  • Administration

    p.o.

Customer Product Validation

Data from [Data independently produced by , , Front Mol Neurosci, 2017, 10:417]

Data from [Data independently produced by , , Oncol Rep, 2017, 38(5):2705-2716]

Data from [Data independently produced by , , ONCOLOGY REPORTS, 2017, 38: 2705-2716]

Selleck's PF-3758309 has been cited by 32 publications

FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation [ Oncogene, 2023, 42(39):2878-2891] PubMed: 37596321
FBXO28 suppresses liver cancer invasion and metastasis by promoting PKA-dependent SNAI2 degradation [ Oncogene, 2023, 10.1038/s41388-023-02809-0] PubMed: 37596321
Mechanism by Which PF-3758309, a Pan Isoform Inhibitor of p21-Activated Kinases, Blocks Reactivation of HIV-1 Latency [ Biomolecules, 2023, 13(1)100] PubMed: 36671485
Mechanism by Which PF-3758309, a Pan Isoform Inhibitor of p21-Activated Kinases, Blocks Reactivation of HIV-1 Latency [ Biomolecules, 2023, 13(1)100] PubMed: 36671485
Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation [ Sci Adv, 2023, 9(7):eade8939] PubMed: 36791204
Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma [ Blood Sci, 2023, 5(4):249-257] PubMed: 37941919
PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways [ Biochem Biophys Rep, 2023, 10.1016/j.bbrep.2023.101544] PubMed: 37720313
PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/β-catenin, p-ERK/MAPK and p-AKT/PI3K pathways [ Biochem Biophys Rep, 2023, 35:101544] PubMed: 37720313
Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment [ Nat Cancer, 2022, 3(3):318-336] PubMed: 35122074
PFN1 Inhibits Myogenesis of Bovine Myoblast Cells via Cdc42-PAK/JNK [ Cells, 2022, 11(20)3188] PubMed: 36291059

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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