TDZD-8

TDZD-8 is an inhibitor of glycogen synthase kinase-3β (GSK-3β) with IC50 value of 1.4μM [1].

TDZD-8 is a potent inhibitor of GSK-3β. It is found to act as a noncompetitive inhibitor of ATP binding. TDZD-8 is selective against GSK-3β over other protein kinases including PKA, casein kinase II and cyclin dependent kinase 1 (Cdk-1/cyclin B). However, it is also reported that TDZD-8 can inhibit the protein kinase C isoforms PKCβI and PKCδ with IC50 values of 1.4μM and 1.1μM, respectively [1, 2].

In cellular assay, TDZD-8 is found to decrease PDT-induced necrosis of neurons and decrease PDT-induced apoptosis of glial cells through inhibiting GSK-3β as well as PKC. Besides that, TDZD-8 also has anti-leukemia activity in many primary human leukemia cells. It is probably due to its inhibition of PKC and FLT3 [3].

References:
[1] Komandirov M A, Knyazeva E A, Fedorenko Y P, et al. On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3β in photodynamic injury of crayfish neurons and glial cells. Journal of Molecular Neuroscience, 2011, 45(2): 229-235.
[2] Martinez A, Alonso M, Castro A, et al. First non-ATP competitive glycogen synthase kinase 3 β (GSK-3β) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease. Journal of medicinal chemistry, 2002, 45(6): 1292-1299.
[3] Guzman M L, Li X, Corbett C A, et al. Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1, 2, 4-thiadiazolidine, 3, 5 dione (TDZD-8). Blood, 2007, 110(13): 4436-4444.

GSK-3beta inhibitor TDZD-8 reduces neonatal hypoxic-ischemic brain injury in mice.[Pubmed:28256059]

CNS Neurosci Ther. 2017 May;23(5):405-415.

AIMS: Glycogen synthase kinase 3beta (GSK-3beta) is activated following hypoxic-ischemic (HI) brain injury. TDZD-8 is a specific GSK-3beta inhibitor. Currently, the impact of inhibiting GSK-3beta in neonatal HI injury is unknown. We aimed to investigate the effect of TDZD-8 following neonatal HI brain injury. METHODS: Unilateral common carotid artery ligation followed by hypoxia was used to induce HI injury in postnatal day 7 mouse pups pretreated with TDZD-8 or vehicle. The infarct volume, whole-brain imaging, Nissl staining, and behavioral tests were used to evaluate the protective effect of TDZD-8 on the neonatal brain and assess functional recovery after injury. Western blot was used to evaluate protein levels of phosphorylated protein kinase B (Akt), GSK-3beta, and cleaved caspase-3. Protein levels of cleaved caspase-3, neuronal marker, and glial fibrillary acidic protein were detected through immunohistochemistry. RESULTS: Pretreatment with TDZD-8 significantly reduced brain damage and improved neurobehavioral outcomes following HI injury. TDZD-8 reversed the reduction of phosphorylated Akt and GSK-3beta, and the activation of caspase-3 induced by hypoxia-ischemia. In addition, TDZD-8 suppressed apoptotic cell death and reduced reactive astrogliosis. CONCLUSION: TDZD-8 has the therapeutic potential for hypoxic-ischemic brain injury in neonates. The neuroprotective effect of TDZD-8 appears to be mediated through its antiapoptotic activity and by reducing astrogliosis.

Imaging pulmonary NF-kappaB activation and therapeutic effects of MLN120B and TDZD-8.[Pubmed:21966423]

PLoS One. 2011;6(9):e25093.

NF-kappaB activation is a critical signaling event in the inflammatory response and has been implicated in a number of pathological lung diseases. To enable the assessment of NF-kappaB activity in the lungs, we transfected a luciferase based NF-kappaB reporter into the lungs of mice or into Raw264.7 cells in culture. The transfected mice showed specific luciferase expression in the pulmonary tissues. Using these mouse models, we studied the kinetics of NF-kappaB activation following exposure to lipopolysaccharide (LPS). The Raw264.7 cells expressed a dose-dependent increase in luciferase following exposure to LPS and the NF-kappaB reporter mice expressed luciferase in the lungs following LPS challenge, establishing that bioluminescence imaging provides adequate sensitivity for tracking the NF-kappaB activation pathway. Interventions affecting the NF-kappaB pathway are promising clinical therapeutics, thus we further examined the effect of IKK-2 inhibition by MLN120B and glycogen synthase kinase 3 beta inhibition by TDZD-8 on NF-kappaB activation. Pre-treatment with either MLN120B or TDZD-8 attenuated NF-kappaB activation in the pulmonary tissues, which was accompanied with suppression of pro-inflammatory chemokine MIP-1ss and induction of anti-inflammatory cytokine IL-10. In summary, we have established an imaging based approach for non-invasive and longitudinal assessment of NF-kappaB activation and regulation during acute lung injury. This approach will potentiate further studies on NF-kappaB regulation under various inflammatory conditions.

Activation of AKT/GSK3beta pathway by TDZD-8 attenuates kainic acid induced neurodegeneration but not seizures in mice.[Pubmed:25453207]

Neurotoxicology. 2015 Jan;46:44-52.

Activation of glycogen synthase kinase3beta (GSK3beta), an enzyme that regulates a multitude of cellular signaling pathways, is implicated in neurodegenerative processes observed in an array of CNS diseases. We examined the hypothesis that the pathological changes in an acute kainic acid (KA) induced excitotoxicity model, relevant to human temporal lobe epilepsy (TLE), could be sensitive to inhibition of GSK3beta by 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) treatment in Swiss albino mice. Immediate seizure responses due to KA were recorded. Neurodegenerative and morphogenic changes were examined by western blot analysis and light microscopy, respectively, 48 h after KA administration. Although tonic-clonic seizure episodes evoked by KA were unaffected, TDZD-8 pretreatment decreased KA mediated elevation in caspase-3 cleavage as well as increased Bcl2 and phospho-GSK3beta (Ser9; pGSK3beta(Ser9)) expression. Likewise, microscopic examination also revealed that pretreatment with TDZD-8 attenuated cell damage elicited by KA in the CA1, CA3 and DG regions. In all the above parameters, the combined effect of a sub-effective dose of sodium valproate (SVP) with TDZD-8 was higher than that of solitary TDZD-8 treatment. The findings suggest that activated GSK3beta orchestrated neurodegenerative alterations following KA treatment and its inhibition by TDZD-8 affords a distinct neuroprotective profile by activating Akt/GSK3beta pathway which might act upstream of Bax/Bcl2 and caspase-3 pathways. Compounds targeting GSK3beta activity might represent a novel therapeutic option for exploration as an adjunct to conventional anti-epileptic drugs in preventing neurodegenerative processes in TLE.

Inhibition of glioblastoma growth by the thiadiazolidinone compound TDZD-8.[Pubmed:21079728]

PLoS One. 2010 Nov 8;5(11):e13879.

BACKGROUND: Thiadiazolidinones (TDZD) are small heterocyclic compounds first described as non-ATP competitive inhibitors of glycogen synthase kinase 3beta (GSK-3beta). In this study, we analyzed the effects of 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), on murine GL261 cells growth in vitro and on the growth of established intracerebral murine gliomas in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Our data show that TDZD-8 decreased proliferation and induced apoptosis of GL261 glioblastoma cells in vitro, delayed tumor growth in vivo, and augmented animal survival. These effects were associated with an early activation of extracellular signal-regulated kinase (ERK) pathway and increased expression of EGR-1 and p21 genes. Also, we observed a sustained activation of the ERK pathway, a concomitant phosphorylation and activation of ribosomal S6 kinase (p90RSK) and an inactivation of GSK-3beta by phosphorylation at Ser 9. Finally, treatment of glioblastoma stem cells with TDZD-8 resulted in an inhibition of proliferation and self-renewal of these cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that TDZD-8 uses a novel mechanism to target glioblastoma cells, and that malignant progenitor population could be a target of this compound.

TDZD-8 is an inhibitor of GSK-3β, with an IC50 of 2 μM; TDZD-8 shows less potent activities against Cdk-1/cyclin B, CK-II, PKA, and PKC, with all IC50s of >100 μM.

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