| InChI | InChI=1S/C22H18Cl2N8/c1-13-10-29-21(31-13)17-12-30-22(32-20(17)16-4-3-15(23)8-18(16)24)27-7-6-26-19-5-2-14(9-25)11-28-19/h2-5,8,10-12H,6-7H2,1H3,(H,26,28)(H,29,31)(H,27,30,32) |
| Reference | 1:J Cardiovasc Pharmacol. 2016 Dec;68(6):425-432. GSK-3β Inhibitor CHIR-99021 Promotes Proliferation Through Upregulating β-Catenin in Neonatal Atrial Human Cardiomyocytes.Wang S,Ye L,Li M,Liu J,Jiang C,Hong H,Zhu H,Sun Y, PMID: 27575008 DOI: 10.1097/FJC.0000000000000429 <br />
<span>Abstract:</span> BACKGROUND: The renewal capacity of neonate human cardiomyocytes provides an opportunity to manipulate endogenous cardiogenic mechanisms for supplementing the loss of cardiomyocytes caused by myocardial infarction or other cardiac diseases. GSK-3β inhibitors have been recently shown to promote cardiomyocyte proliferation in rats and mice, thus may be ideal candidates for inducing human cardiomyocyte proliferation.METHODS: Human cardiomyocytes were isolated from right atrial specimens obtained during routine surgery for ventricle septal defect and cultured with either GSK-3β inhibitor (CHIR-99021) or β-catenin inhibitor (IWR-1). Immunocytochemistry was performed to visualize 5-ethynyl-2/’-deoxyuridine (EdU)-positive or Ki67-positive cardiomyocytes, indicative of proliferative cardiomyocytes.RESULTS: GSK-3β inhibitor significantly increased β-catenin accumulation in cell nucleus, whereas β-catenin inhibitor significantly reduced β-catenin accumulation in cell plasma. In parallel, GSK-3β inhibitor increased EdU-positive and Ki67-positive cardiomyocytes, whereas β-catenin inhibitor decreased EdU-positive and Ki67-positive cardiomyocytes.CONCLUSIONS: These results indicate that GSK-3β inhibitor can promote human atrial cardiomyocyte proliferation. Although it remains to be determined whether the observations in atrial myocytes could be directly applicable to ventricular myocytes, the current findings imply that Wnt/β-catenin pathway may be a valuable pathway for manipulating endogenous human heart regeneration. <br />
2. Diabetes. 2003 Mar;52(3):588-95. <br />
Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of
glucose transport and utilization in vitro and in vivo. <br />
Ring DB(1), Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder
JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD. <br />
Author information: <br />
(1)Chiron Corporation, Emeryville, California, USA. <br />
Insulin resistance plays a central role in the development of type 2 diabetes,
but the precise defects in insulin action remain to be elucidated. Glycogen
synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin
signaling, and elevated levels of GSK-3 have been reported in skeletal muscle
from diabetic rodents and humans. A limited amount of information is available
regarding the utility of highly selective inhibitors of GSK-3 for the
modification of insulin action under conditions of insulin resistance. In the
present investigation, we describe novel substituted aminopyrimidine derivatives
that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold
selectivity against 20 other protein kinases. These low molecular weight
compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO
cells transfected with the insulin receptor and in primary hepatocytes isolated
from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of
both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors
enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the
insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats.
Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered
blood glucose levels and improved glucose disposal after oral or intravenous
glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or
markedly elevating insulin. Collectively, our results suggest that these
selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the
treatment of the insulin resistance of type 2 diabetes.
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