Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases

Tell, Volkmar; Holzer, Max; Herrmann, Lydia; Mahmoud, Kazem; Schächtele, Christoph; Totzke, Frank; Hilgeroth, Andreas

doi:10.1016/j.bmcl.2012.09.006

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…Following up on the idea to use CDK5 as drug target in melanoma appears even more intriguing since other suitable CDK5 small molecule inhibitors are currently already under development and or in early clinical testing for other indications [11,45,57,58] . Therefore, it is very likely that suitable drugs with known dosing schedules, pharmacokinetics data, and toxicity profiles might soon be available, which could then relatively easily and safely be evaluated in patients suffering from metastatic melanoma.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread—Identification of a Promising Novel therapeutic target

Nolting¹,

Schütte²,

Haarmann³

et al. 2015

Translational Oncology

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Despite considerable progress in recent years, the overall prognosis of metastatic malignant melanoma remains poor, and curative therapeutic options are lacking. Therefore, better understanding of molecular mechanisms underlying melanoma progression and metastasis, as well as identification of novel therapeutic targets that allow inhibition of metastatic spread, are urgently required. The current study provides evidence for aberrant cyclin-dependent kinase 5 (CDK5) activation in primary and metastatic melanoma lesions by overexpression of its activator protein CDK5R1/p35. Moreover, using melanoma in vitro model systems, shRNA-mediated inducible knockdown of CDK5 was found to cause marked inhibition of cell motility, invasiveness, and anchorage-independent growth, while at the same time net cell growth was not affected. In vivo, CDK5 knockdown inhibited growth of orthotopic xenografts as well as formation of lung and liver colonies in xenogenic injection models mimicking systemic metastases. Inhibition of lung metastasis was further validated in a syngenic murine melanoma model. CDK5 knockdown was accompanied by dephosphorylation and overexpression of caldesmon, and concomitant caldesmon knockdown rescued cell motility and proinvasive phenotype. Finally, it was found that pharmacological inhibition of CDK5 activity by means of roscovitine as well as by a novel small molecule CDK5-inhibitor, N-(5-isopropylthiazol-2-yl)-3-phenylpropanamide, similarly caused marked inhibition of invasion/migration, colony formation, and anchorage-independent growth of melanoma cells. Thus, experimental data presented here provide strong evidence for a crucial role of aberrantly activated CDK5 in melanoma progression and metastasis and establish CDK5 as promising target for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread—Identification of a Promising Novel therapeutic target

Nolting¹,

Schütte²,

Haarmann³

et al. 2015

Translational Oncology

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“…Further, we applied MCL clustering algorithm to identify functional modules with proteins forming hub nodes (EGFR, ACTB, CDC2, IRAK2, APOE, ABCA1 and AMPH) which might serve as important candidates related to AD [50]. For instance, CDC2 [109, 110], IRAK2 [111] have been reported in recently published studies with suggestive role in AD pathogenesis. GO analysis was also carried out using 108 genes to identify biological processes, molecular functions and cellular components.…”

Section: Discussionmentioning

confidence: 99%

Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease

et al. 2014

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BackgroundAlzheimer’s disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi-dimensional data and protein-protein interaction (PPI) network modelling.ResultsOur approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108 AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes.ConclusionsWith the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-199) contains supplementary material, which is available to authorized users.

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“…Accumulating evidence suggested that the activities of CDK5 and GSK3β are elevated in AD (Leclerc et al, 2001 ; Tell et al, 2012 ). Many CDK5 and GSK3β inhibitors are reported to produce anti-AD neuroprotective effects (Leclerc et al, 2001 ; Tell et al, 2012 ). Thus, 7Bio, a moderate inhibitor of CDK5 and GSK3β, might also exhibit anti-AD property.…”

Section: Discussionmentioning

confidence: 99%

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice

Li-ping

Huang

Shentu

et al. 2017

Front. Mol. Neurosci.

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Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3–23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.

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Multitargeted drug development: Discovery and profiling of dihydroxy substituted 1-aza-9-oxafluorenes as lead compounds targeting Alzheimer disease relevant kinases

Cited by 14 publications

References 23 publications

Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread—Identification of a Promising Novel therapeutic target

Cyclin-Dependent Kinase 5 (CDK5) Controls Melanoma Cell Motility, Invasiveness, and Metastatic Spread—Identification of a Promising Novel therapeutic target

Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice

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