Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma

Sestito, Simona; Daniele, Simona; Nesi, Giulia; Zappelli, Elisa; Maio, Danilo Di; Marinelli, Luciana; Digiacomo, Maria; Lapucci, Annalina; Martini, Claudia; Novellino, Ettore; Rapposelli, Simona

doi:10.1016/j.ejmech.2016.04.003

Cited by 21 publications

(27 citation statements)

References 48 publications

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“…However, some molecules ( Figure 2 ) have already reached advanced stages of preclinical development with proven efficacy in vivo against GBM [ 19 , 20 , 21 , 22 ]. Considering described targets several protein kinases have been referred such as phosphoinositide 3-kinase (PI3K), dual-specificity tyrosine-regulated kinases (DYRK), pyruvate dehydrogenase kinase 1 (PDK1), casein kinase II (CK2), c-Src, protein kinase B (Akt), focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) [ 23 , 24 , 25 , 26 ]. In addition, many cellular pathways, enzymes and processes have also been investigated, such as G-quadruplexes, histone deacetylases (HDACs), heat shock protein 90 (HSP90), microtubules, via NF-kB, p53, among others [ 23 , 24 , 25 , 26 , 27 , 28 ].…”

Section: Treatment Of Gliomamentioning

confidence: 99%

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

et al. 2021

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Marine organisms are able to produce a plethora of small molecules with novel chemical structures and potent biological properties, being a fertile source for discovery of pharmacologically active compounds, already with several marine-derived agents approved as drugs. Glioma is classified by the WHO as the most common and aggressive form of tumor on CNS. Currently, Temozolomide is the only chemotherapeutic option approved by the FDA even though having some limitations. This review presents, for the first time, a comprehensive overview of marine compounds described as anti-glioma agents in the last decade. Nearly fifty compounds were compiled in this document and organized accordingly to their marine sources. Highlights on the mechanism of action and ADME properties were included. Some of these marine compounds could be promising leads for the discovery of new therapeutic alternatives for glioma treatment.

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Section: Treatment Of Gliomamentioning

confidence: 99%

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

et al. 2021

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“…Overexpression of PDK1 correlates with an aggressive phenotype and poor prognosis 7 . Therefore, drugs targeting the PDK1/Akt pathway have emerged as one of the potential treatments for GBM [8][9][10] . However, specific target drugs, including those against PDK1, did not show a significant clinical efficacy 11 , and preclinical studies on PDK1 inhibitors have been hampered by the lack of peculiar proof-of-concept molecules 5,[12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells

Daniele¹,

Sestito²,

Pietrobono³

et al. 2016

ACS Chem. Neurosci.

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The poor prognosis of glioblastoma multiforme (GBM) is mainly attributed to drug resistance mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multitarget compounds able to both affect different deregulated pathways and the GSC subpopulation could escape tumor resistance and, most importantly, eradicate the stem cell reservoir. In this respect, the simultaneous inhibition of phosphoinositide-dependent kinase-1 (PDK1) and aurora kinase A (AurA), each one playing a pivotal role in cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM resistance and recurrence. Herein, the cross-talk between these pathways was investigated, using the single-target reference compounds MP7 (PDK1 inhibitor) and Alisertib (AurA inhibitor). Furthermore, a new ligand, SA16, was identified for its ability to inhibit the PDK1 and the AurA pathways at once, thus proving to be a useful tool for the simultaneous inhibition of the two kinases. SA16 blocked GBM cell proliferation, reduced tumor invasiveness, and triggered cellular apoptosis. Most importantly, the AurA/PDK1 blocker showed an increased efficacy against GSCs, inducing their differentiation and apoptosis. To the best of our knowledge, this is the first report on combined targeting of PDK1 and AurA. This drug represents an attractive multitarget lead scaffold for the development of new potential treatments for GBM and GSCs.

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“…We have previously carried out a protein kinase activity screen for SA16 and IB35 (SelectScreen Kinase Profiling Service, Invitrogen-Life Technologies). Among almost 60 protein kinases screened, both SA16 and IB35 (500 nM) displayed a very high inhibitory activity towards PDK1 and Aurora kinase A and they did not affect (percentage of inhibition <20%) any of all the other tested kinases [19,20]. Furthermore, results from SelectScreen Kinase Profiling Service (Invitrogen-Life Technologies) 10-point titration showed that the IC 50 s of SA16 and IB35 towards PDK1 were 416 nM and 112 nM respectively, whereas the corresponding IC 50 s toward Aurora kinase A were 39 nM and 289 nM, respectively [19,20].…”

Section: Resultsmentioning

confidence: 99%

Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation

Casari

Domenichini

Sestito

et al. 2019

Cancers

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Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required.

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Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma

Cited by 21 publications

References 48 publications

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells

Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation

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