PDK4-IN-1 hydrochloride

Product NamePDK4-IN-1 hydrochloride
CAS2310262-11-2
MFC22H20ClN3O2
MW393.87
EINECS
MOL File2310262-11-2.mol

Chemical Properties

storage temp.	Inert atmosphere,Room Temperature
solubility	DMSO: 125 mg/mL (317.36 mM)
form	Solid
color	Light yellow to yellow
Water Solubility	H2O: 2mg/mL, clear (Warmed)
InChIKey	ZIMLKZKPNALXKK-UHFFFAOYSA-N
SMILES	Cl.[n]2(ncc(c2)c3c4c(ccc3)C(=O)c5c(cccc5)C4=O)C1CCNCC1

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Uses

PDK4-IN-1 hydrochloride is an anthraquinone derivative and a potent and orally active pyruvate dehydrogenase kinase 4 (PDK4) inhibitor with an IC50 value of 84 nM. PDK4-IN-1 hydrochloride potently represses cellular transformation and cellular proliferation and induces apoptosis. PDK4-IN-1 hydrochloride has antidiabetic, anticancer and anti-allergic activity[1].

Biological Activity

PDK4-IN-1 hydrochloride is an anthraquinone derivative and a potent, orally active inhibitor of pyruvate dehydrogenase kinase 4 (PDK4) with IC50 of 84 nM. It effectively inhibits cell transformation and cell proliferation and induces apoptosis. It has antidiabetic, anticancer and antiallergic effects.

in vitro

PDK4-IN-1 (Compound 8c; 50 μM; 0-72 hours; HCT116 and RKO cells) treatment significantly impedes the proliferation of human colon cancer cell lines, HCT116 and RKO. The colony formation efficiency in HCT116 and RKO cells Is significantly reduced after treatment of PDK4-IN-1.
PDK4-IN-1 (Compound 8c; 10-50 μM; 24 hours; HCT116 and RKO cells) treatment dose-dependently increased apoptosis.
PDK4-IN-1 (Compound 8c; 10 μM; 24 hours; HEK293T cells) treatment inhibits phosphorylation of Ser ²³² , Ser ²⁹³ , and Ser ³⁰⁰ of PDHE1α.
10 μM of PDK4-IN-1 (Compound 8c) significantly increased p-Akt in AML12 cells.
PDK4-IN-1 (compound 8c)-induced phosphorylation of p53 on serine 15 is a dose-dependent response in both HCT116 and RKO cells. PDK4-IN-1 decreases the expression of BCL-xL and increases the expression of BAX. Cleavage of PARP1 and caspase 3 are increased by PDK4-IN-1.

Cell Viability Assay

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Cell Line:	HCT116 and RKO cells
Concentration:	50 μM
Incubation Time:	0 hour, 24 hours, 48 hours, 72hours
Result:	Significantly impeded the proliferation of human colon cancer cell lines, HCT116 and RKO.

Apoptosis Analysis

< td class="col2"> 24 hours

Cell Line:	HCT116 and RKO cells
Concentration:	10 μM, 25 μM, 50 μM
Incubation Time:
Result:	Dose-depend ently increased apoptosis.

Western Blot Analysis < /p>

Cell Line:	HEK293T human embryonic kidney cells
Concentration:	10 μM
Incubation Time: < /td>	24 hours
Result:	Inhibited phosphorylation of Ser ²³² , Ser ²⁹³ , and Ser ³⁰⁰ of PDHE1α.

in vivo

PDK4-IN-1 (Compound 8c; 100 mg/kg; oral administration; daily; for 1 week; C57BL/6J mice) treatment significantly improves glucose tolerance.
Pre-incubation with it (compound 8c) dose-dependently inhibits the release of β-hexosaminidase from IgE/antigen-activated BMMCs, showing that the absorbance values are 0.26, 0.20, and 0.126 in IgE/Ag, 10 μM, and 20 μM PDK4- IN-1-treated BMMCs.
The pharmacokinetic (PK) profiles of PDK4-IN-1 (compound 8c) are evaluated in rat. PDK4-IN-1 shows good bioavailability (64%), long half-life ( >7 h), and moderate clearance (CL of 0.69) in rats.

td>

Animal Model:	C57BL/6J mice (8 -week old) fed with high-fat diet
Dosage:	100 mg/kg
Administration:	Oral adminis tration; daily; for 1 week
Result:	Significantly improved glucose tolerance.

target

IC50: 84 nM (Pyruvate dehydrogenase kinase 4 (PDK4))

References

[1] Lee D, et al. Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases. J Med Chem. 2019 Jan 24;62(2):575-588. DOI:10.1021/acs.jmedchem.8b01168

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