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 (IC
50 = 230 nM), Lck (IC
50 = 470 nM), and cyclin-dependent kinases (Cdks). Inhibits Cdk1/cyclin B (IC
50 = 400 nM), Cdk2/cyclin A (IC
50 = 680 nM), Cdk2/cyclin E (IC
50 = 7.5 μM), and Cdk5/p25 (IC
50 = 850 nM). Also inhibits other kinases such as c-Src (IC
50 = 15 μM), casein kinase II (IC
50 = 20 μM), ERK1 (IC
50 = 20 μM), and ERK2 (IC
50 = 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.
Synthesis
A suspension was formed in glacial acetic acid (10 ml) with 3,4-dihydrobenzo[b]azepine-2,5-dione (1.05 g, 6 mmol) and p-bromophenylhydrazine (7 mmol). The mixture was stirred and reacted at 70°C for 1 hour. After completion of the reaction, it was cooled to room temperature and 0.5 ml of concentrated hydrochloric acid was added to continue stirring. Subsequently, H2SO4 was added at 70°C and the reaction was kept for 1 hour. After the reaction mixture was cooled, it was poured into 50 ml of 10% sodium acetate solution and precipitated. The yellow crystalline product was collected by diafiltration. The product was 9-bromo-7,12-dihydrobenzo[2,3]azepino[4,5-b]indol-6(5H)-one in 58% yield and melting point >330°C (1,4-dioxane). Molecular formula: C16H11BrN2O (327.2).IR spectrum showed: 3220 cm-1 (NH stretching vibration); 1640 cm-1 (C=O stretching vibration).1H NMR (δ, ppm): 11.75 (s, 1H, NH), 10.05 (s, 1H, NH), 7.89 (d, 1H, J = 1.5Hz, C-8- H), 7.74 (bd, 1H, J = 7.5 Hz, Ar-H), 7.41-7.34 (m, 2H, Ar-H), 7.30-7.21 (m, 3H, Ar-H), 3.50 (s, 2H, CH2).
References
[1] D W ZAHAREVITZ. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases.[J]. Cancer research, 1999, 59 11: 2566-2569.
[2] CHRISTIANE SCHULTZ. Paullones, a Series of Cyclin-Dependent Kinase Inhibitors: Synthesis, Evaluation of CDK1/Cyclin B Inhibition, and in Vitro Antitumor Activity[J]. Journal of Medicinal Chemistry, 1999, 42 15: 2909-2919. DOI:
10.1021/jm9900570[3] JENNY BAIN. The specificities of protein kinase inhibitors: an update.[J]. Biochemical Journal, 2003, 371 Pt 1: 199-204. DOI:
10.1042/bj20021535[4] COSTAS A LYSSIOTIS. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 22: 8912-8917. DOI:
10.1073/pnas.0903860106[5] U. PFISTERER. Small molecules increase direct neural conversion of human fibroblasts[J]. Scientific Reports, 2016, 6 1. DOI:
10.1038/srep38290[6] SEUNGJIN CHOI. 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.[J]. ACS Applied Materials & Interfaces, 2018: 1339. DOI:
10.3389/fimmu.2018.01339
![1H-[1]-BENZAZEPHE-2,5(3H, 4H)-DIONE](/CAS/GIF/16511-38-9.gif)
