VPS34 inhibitor 1 (Compound 19)

Catalog No.S8456 Batch:S845604

Technical Data

Formula	C₂₁H₂₅N₇O
Molecular Weight	391.47	CAS No.	1383716-46-8
Solubility (25°C)*	In vitro	DMSO	78 mg/mL (199.24 mM)
		Water	Insoluble
		Ethanol	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

VPS34 inhibitor 1 (Compound 19, PIK-III analogue) is a potent and selective inhibitor of VPS34 with an IC50 of 15 nM.

Targets

VPS34 ^[1]
(Cell-free assay)

15 nM

In vitro

Compound 19 is extraordinarily selective over other lipid and protein kinases. The ability of compound 19 to prevent the degradation of autophagy substrates p62, NCOA4, NBR1, NDP52, and FTH1 is similar to PIK-III. In addition, treatment of cells with compound 19 leads to an increase in the lipidated and nonlipidated forms of LC3 similar to previous reports using PIK-III^[1].

In vivo

The pharmacokinetic profile of analogue 19 is determined in C57BL/6 mice. After oral administration at 10 mg/kg, the compound is rapidly absorbed and showed moderate mean systemic clearance (30 mL/min/kg, approximately 33% of hepatic blood flow), with good oral bioavailability (F% = 47). Based on these PK parameters and the cellular activity, compound 19 constitutes a suitable candidate for in vivo studies. Upon oral administration of compound 19 at 50 mg/kg twice a day (BID) for 7 days, LC3-II accumulates consistent with reduced autophagic capacity in time-dependent manner. It inhibits autophagy in vivo^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines U2OS cells Concentrations 0, 1, 5, 10 μM Incubation Time 24 h Method For inhibitor assay, cells are plated and the following day when cells had reached 90%, are treated with dimethyl sulfoxide (DMSO, vehicle) or the indicated concentration of PIK-III or Compound 19, both dissolved in DMSO. 24 hours later, cells are lysed in RIPA supplemented with 1% SDS and mini-EDTA protease inhibitors, homogenized by passage through a Qiashredder column and the protein is quantified by DC Lowry protein assay.
Animal Study:^{^[1]}	Animal Models C57BL/6 Mice Dosages 10 mg/kg(p.o.) or 2 mg/kg(I.V.) Administration oral administration or I.V.

Cell Assay:^{^[1]}

Cell lines
U2OS cells
Concentrations
0, 1, 5, 10 μM
Incubation Time
24 h
Method
For inhibitor assay, cells are plated and the following day when cells had reached 90%, are treated with dimethyl sulfoxide (DMSO, vehicle) or the indicated concentration of PIK-III or Compound 19, both dissolved in DMSO. 24 hours later, cells are lysed in RIPA supplemented with 1% SDS and mini-EDTA protease inhibitors, homogenized by passage through a Qiashredder column and the protein is quantified by DC Lowry protein assay.

Animal Study:^{^[1]}

Animal Models
C57BL/6 Mice
Dosages
10 mg/kg(p.o.) or 2 mg/kg(I.V.)
Administration
oral administration or I.V.

References

[1] Honda A, et al. ACS Med Chem Lett. 2015, 7(1):72-6.

Customer Product Validation

: Data from [Data independently produced by , , Oncotarget, 2017, 8(24):38099-38112]

Selleck's VPS34 inhibitor 1 (Compound 19) has been cited by 8 publications

PROX1 induction by autolysosomal activity stabilizes persister-like state of colon cancer via feedback repression of the NOX1-mTORC1 pathway [ Cell Rep, 2023, S2211-1247(23)00530-2]	PubMed: 37224811
Upregulation of the EGFR/MEK1/MAPK1/2 signaling axis as a mechanism of resistance to antiestrogen‑induced BimEL dependent apoptosis in ER+ breast cancer cells [ Int J Oncol, 2023, 62(2)20]	PubMed: 36524361
Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission [ EMBO J, 2022, 10.15252/embj.2021109352]	PubMed: 35318705
Subtractive CRISPR screen identifies the ATG16L1/vacuolar ATPase axis as required for non-canonical LC3 lipidation [ Cell Rep, 2021, 37(4):109899]	PubMed: 34706226
Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells [ Cell, 2020, S0092-8674(20)31394-5]	PubMed: 33147445
Subtractive CRISPR screen identifies factors involved in non-canonical LC3 lipidation. [ bioRxiv, 2020, 10.1101/2020.11.18.388306]	PubMed: None
The Chick Chorioallantoic Membrane (CAM) Assay as a Three-dimensional Model to Study Autophagy in Cancer Cells [ Bio Protoc, 2019, 9(13):e3290]	PubMed: 33654803
Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R. [Filippakis H, et al. Oncotarget, 2017, 8(24):38099-38112]	PubMed: 28498820

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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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