AZD2858 is a potent orally active glycogen synthase kinase 3 (GSK-3) inhibitor. AZD2858 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. AZD2858 caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. Treatment (1 μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily (total BMC: 172% of control; p<0.001).
|Source||Biochem Biophys Res Commun (2014). Figure 4. AZD2858|
|Cell Lines||U2OS cells|
|Concentrations||25 and 40 μM|
|Incubation Time||24 h|
|Results||As observed with CCCP, AZD2858 induced PRC(FL), a result consistent with the negative control of PRC expression by GSK-3.|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats.
Gilmour PS, et al. Toxicol Appl Pharmacol. 2013 Jul 18;272(2):399-407. PMID: 23872097.
Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation.
Sisask G, et al. Bone. 2013 May;54(1):126-32. PMID: 23337038.
GSK-3 inhibition by an orally active small molecule increases bone mass in rats.
Marsell R, et al. Bone. 2012 Mar;50(3):619-27. PMID: 22142634.
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TDZD-8 is a non-ATP competitive GSK-3β inhibitor with IC50 of 2 μM; minimal inhibitory effect observed on CDK1, casein kinase II, PKA and PKC.
LY2090314 is a potent GSK-3 inhibitor for GSK-3α/β with IC50 of 1.5 nM/0.9 nM; may improve the efficacy of platinum-based chemotherapy regimens. Phase 1/2.
AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively.
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