KPT 9274 (ATG-019)

Catalog No.S8444 Batch:S844402

Technical Data

Formula	C₃₅H₂₉F₃N₄O₃
Molecular Weight	610.62	CAS No.	1643913-93-2
Solubility (25°C)*	In vitro	DMSO	100 mg/mL (163.76 mM)
		Ethanol	100 mg/mL (163.76 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

KPT 9274 ( ATG-019) is an orally bioavailable small molecule that is a non-competitive dual inhibitor of PAK4 and NAMPT. It shows an IC50 of ~120 nM for NAMPT in a cell-free enzymatic assay.

Targets

PAK4 ^[1] (Cell-free assay)	NAMPT ^[1] (Cell-free assay)
	~120 nM

In vitro

KPT-9274 interferences with PAK4 and NAD biosynthetic pathways results in reduction of G2/M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. The inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc^[1].

In vivo

KPT-9274 administration to a 786-O (VHL-mut) human RCC xenograft model leads to dose-dependent inhibition of tumor growth with no apparent toxicity^[1]. It also shows remarkable anti-tumor activity in sub-cutaneous xenograft models of pancreatic ductal adenocarcinoma (PDAC) cell lines and cancer stem cells as a single agent. KPT-9274 possesses desirable PK properties and is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally^[2].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines 786-0, ACHN, Caki-1 and U-2 OS cells Concentrations 1μM and 5μM Incubation Time 12 hours Method The in vitro cell migration and invasion assays were performed using transwell chambers. For the transwell migration assay, 1.5×10⁴ cells were seeded on top of the polycarbonate filters, and 0.6 ml of growth medium with DMSO or KPT-9274 (1μM and 5μM) was added to both the upper and lower wells. After incubation for 12 hours, the filters were swabbed with a cotton swab, fixed with methanol, and then stained with Giemsa solution. For the in vitro invasion assay, filters were coated with Matrigel, and 2.5×10⁴ cells were seeded onto the Matrigel and incubated for 20 hours. The cells attached to the lower surface of the filter were counted under a light microscope (10× magnification).
Animal Study:^{^[1]}	Animal Models 786-O (VHL-mut) human RCC xenograft model (nude mice) Dosages 100 and 200 mg/kg Administration by oral gavage

Cell Assay:^{^[1]}

Cell lines
786-0, ACHN, Caki-1 and U-2 OS cells
Concentrations
1μM and 5μM
Incubation Time
12 hours
Method
The in vitro cell migration and invasion assays were performed using transwell chambers. For the transwell migration assay, 1.5×10⁴ cells were seeded on top of the polycarbonate filters, and 0.6 ml of growth medium with DMSO or KPT-9274 (1μM and 5μM) was added to both the upper and lower wells. After incubation for 12 hours, the filters were swabbed with a cotton swab, fixed with methanol, and then stained with Giemsa solution. For the in vitro invasion assay, filters were coated with Matrigel, and 2.5×10⁴ cells were seeded onto the Matrigel and incubated for 20 hours. The cells attached to the lower surface of the filter were counted under a light microscope (10× magnification).

Animal Study:^{^[1]}

Animal Models
786-O (VHL-mut) human RCC xenograft model (nude mice)
Dosages
100 and 200 mg/kg
Administration
by oral gavage

References

[1] Abu Aboud O, et al. Mol Cancer Ther. 2016, 15(9):2119-29.

Selleck's KPT 9274 (ATG-019) has been cited by 6 publications

Genomic and transcriptomic profiling of peripheral T cell lymphoma reveals distinct molecular and microenvironment subtypes [ Cell Rep Med, 2024, 5(2):101416]	PubMed: 38350451
Inhibition of nicotinamide dinucleotide salvage pathway counters acquired and intrinsic poly(ADP-ribose) polymerase inhibitor resistance in high-grade serous ovarian cancer [ Sci Rep, 2023, 13(1):3334]	PubMed: 36849518
M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism [ Sci Adv, 2023, 9(15):eadf8522]	PubMed: 37058562
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
Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma [ NAT CANCER, 2021, 2, 83–97]	PubMed: None

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