KENPAULLONE

Description

Kenpaullone (142273-20-9) inhibits GSK-3β (IC50=0.23 μM) as well as several cyclin-dependent kinases (CDKs), IC50=0.4, 0.68 and 0.85 μM for cdk1, cdk2 and cdk5 respectively.1-3 Induces pluripotent stem cells from somatic cells4 and increases direct neural conversion of human fibroblasts5 when used with other small molecules. Inhibits Kruppel-Like Factor 4 (KLF4) reducing autoimmune arthritis in the collagen-induced arthritis mouse model.6

Chemical Properties

Tan Solid

Uses

Kenpaullone has been used:

• as a glycogen synthase kinase 3 (GSK3)/ cyclin-dependent kinase (CDK) inhibitor to study its effects on human neural progenitor cell lines
• as an inhibitor of Krupple-like factor 4 (KLF4) in Gs-coupled designer GPCR (Gs DREADD= GsD) Agouti-related peptide (GsD-AgRP) mice
• as a GSK3/CDK inhibitor to study its effects on the sea urchin embryo development

Uses

The paullones are a novel class of kinase inhibitors, initially identified as CDK inhibitors. Kenpaullone has been found to be a useful GSK-3? inhibitor (IC50=23nM).

Definition

ChEBI: Kenpaullone is an indolobenzazepine that is paullone in which the hydrogen at position 9 is replaced by a bromo substituent. It is an ATP-competitive inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3beta (GSK3beta). It has a role as a geroprotector, an EC 2.7.11.26 (tau-protein kinase) inhibitor, a cardioprotective agent and an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor. It is an indolobenzazepine, a lactam and an organobromine compound. It is functionally related to a paullone.

General Description

A potent, cell-permeable, and reversible inhibitor of glycogen synthase kinase-3β (IC₅₀ = 230 nM), Lck (IC₅₀ = 470 nM), and cyclin-dependent kinases (Cdks). Inhibits Cdk1/cyclin B (IC₅₀ = 400 nM), Cdk2/cyclin A (IC₅₀ = 680 nM), Cdk2/cyclin E (IC₅₀ = 7.5 μM), and Cdk5/p25 (IC₅₀ = 850 nM). Also inhibits other kinases such as c-Src (IC₅₀ = 15 μM), casein kinase II (IC₅₀ = 20 μM), ERK1 (IC₅₀ = 20 μM), and ERK2 (IC₅₀ = 9 μM). Inhibition is competitive with respect to ATP binding.

Biological Activity

Potent inhibitor of CDK1/cyclin B and GSK-3 β (IC 50 values are 0.4 and 0.23 μ M respectively). Also inhibits CDK2/cyclin A, CDK2/cyclin E and CDK5/cyclin/p35 (IC 50 values are 0.68, 7.5 and 0.85 μ M respectively). Selective over c-src (IC 50 = 15 μ M), casein kinase 2 (IC 50 = 20 μ M), ERK1 (IC 50 = 20 μ M), ERK2 (IC 50 = 9 μ M) and a range of other protein kinases (IC 50 values > 35 μ M). Generates induced pluripotent stem cells (iPSCs) from somatic cells when used in combination with reprogramming factors; can replace Klf4.

Biochem/physiol Actions

Kenpaullone is also an inhibitor of glycogen synthase kinase 3β (GSK3β).?It also inhibits cyclin-dependent kinase 1 (CDK1/cyclin B), CDK2/cyclin A, CDK2/cyclin E, and CDK5/p25, majorly by competitive inhibition of adenosine triphosphate (ATP) binding.

storage

Room temperature

References

Zaharevitz et al. (1999), Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases; Cancer Res. 59 2566 Schultz et al. (1999) Paullones, a series of cyclin-dependent kinase inhibitor: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity; J.Med.Chem. 42 2909 Bain et al. (2003), The specificities of protein kinase inhibitors: an update; J. 371(Pt. 1) 199 Lyssiotis et al. (2009) Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4; Natl. Acad. Sci. USA 106 8912 Pfisterer et al. (2016), Small molecules increase direct neural conversion of human fibroblasts; Rep. 6 38290 Choi et al. (2018), Kruppel-Like Factor 4 Positively Regulates Autoimmune Arthritis in Mouse Models and Rheumatoid Arthritis in Patients via Modulating Cell Survival and Inflammation Factors of Fibroblast-Like Synoviocyte; Immunol. 9 1339