Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme

Sestito, Simona; Nesi, Giulia; Daniele, Simona; Martelli, Alma; Digiacomo, Maria; Borghini, Alice; Pietra, Daniele; Calderone, Vincenzo; Lapucci, Annalina; Falasca, Marco; Parrella, Paola; Notarangelo, Angelo; Breschi, Maria Cristina; Macchia, Marco; Martini, Claudia; Rapposelli, Simona

doi:10.1016/j.ejmech.2015.10.020

Cited by 42 publications

(35 citation statements)

References 33 publications

(62 reference statements)

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“…The antineoplastic effects of InsP 5 were validated in vivo, where administration of the drug in an ovarian cancer xenograft resulted in growth inhibition akin to cisplatin [ 96 ]. Moreover, derivatives of 2-oxindole (OXIDs) ( Figure 4 B), have been shown to disrupt the PDK1/Akt pathway and comprise good candidates for non-small cell lung cancer treatment [ 97 ], and these results initiated studies for the synthesis and assessment of new derivatives within the same family, which gave rise to promising candidates for the targeting of glioblastoma multiforme (GBM) [ 98 ].…”

Section: Pdk1 Oncogenic Signaling In Chemoresistance: Beyond Aktmentioning

confidence: 99%

Targeting PDK1 for Chemosensitization of Cancer Cells

Emmanouilidi

Falasca

2017

Cancers

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Despite the rapid development in the field of oncology, cancer remains the second cause of mortality worldwide, with the number of new cases expected to more than double in the coming years. Chemotherapy is widely used to decelerate or stop tumour development in combination with surgery or radiation therapy when appropriate, and in many cases this improves the symptomatology of the disease. Unfortunately though, chemotherapy is not applicable to all patients and even when it is, there are many cases where a successful initial treatment period is followed by chemotherapeutic drug resistance. This is caused by a number of reasons, ranging from the genetic background of the patient (innate resistance) to the formation of tumour-initiating cells (acquired resistance). In this review, we discuss the potential role of PDK1 in the development of chemoresistance in different types of malignancy, and the design and application of potent inhibitors which can promote chemosensitization.

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Section: Pdk1 Oncogenic Signaling In Chemoresistance: Beyond Aktmentioning

confidence: 99%

Targeting PDK1 for Chemosensitization of Cancer Cells

Emmanouilidi

Falasca

2017

Cancers

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“…In a very recent study, a 2-oxindole derivative was shown to inhibit PI3K/AKT pathway and its downstream effectors: CHK1, GSK3α, GSK3β and treatment with this compound reduced cell growth of GBM cells. Moreover, this compound decreased GSCs self-renewal and proliferation triggering both apoptosis and differentiation of the stem cell subpopulation [55]. …”

Section: Akt and Gsk3β As Therapeutic Targets In Gbmmentioning

confidence: 99%

AKT/GSK3β Signaling in Glioblastoma

Majewska

Szeliga

2016

Neurochem Res

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Glioblastoma (GBM) is the most aggressive of primary brain tumors. Despite the progress in understanding the biology of the pathogenesis of glioma made during the past decade, the clinical outcome of patients with GBM remains still poor. Deregulation of many signaling pathways involved in growth, survival, migration and resistance to treatment has been implicated in pathogenesis of GBM. One of these pathways is phosphatidylinositol-3 kinases (PI3K)/protein kinase B (AKT)/rapamycin-sensitive mTOR-complex (mTOR) pathway, intensively studied and widely described so far. Much less attention has been paid to the role of glycogen synthase kinase 3 β (GSK3β), a target of AKT. In this review we focus on the function of AKT/GSK3β signaling in GBM.

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“…Compounds with substituted derivatives of 2-oxindole nucleus have showed apoptotic action in vitro against cancer cell lines along with cell shrinkage [15]. Oxindole derivatives have been used as anticancer agents in lung cancer [16]. Antitumor activity centered around ligands with oxindole nucleus central core are suggested to disrupt the PDK/Akt pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Antitumor activity centered around ligands with oxindole nucleus central core are suggested to disrupt the PDK/Akt pathway. The activity of compounds is related to the presence of substituents at position 3 of the oxindole nucleus [16]. The indoles and its modifications or derived compounds possess pharmacophore activities with interesting pharmacological, antimicrobial [17,18], and anticancer activities which are not yet reported.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking of Hyrtimomine a-K From Marine Sponge Hyrtios Spp. As Anticancer Target of Phosphoinositide-Dependent Kinase 1

Adiga

2019

Asian J Pharm Clin Res

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Objective: The hyrtimomine A-K class of indole-based compounds extracted from Hyrtios spp. of sponges from the sea has not been studied for their anticancer properties. Phosphoinositide-dependent kinase 1 (PDK1) is a master regulator of many types of cancer. Compounds currently targeting PDK1 are currently of poor specificity and solubility. Hence, molecular docking to look for new compounds inhibiting PDK1 from the marine environment was carried out. Methods: Target selection for ligands hyrtimomine A-K was done using PharmMapper tool. Molecular docking was done using iGEMDOCK 2.1, a generic evolutionary method of docking. Site moiety mapping was done in SimMap to extract the anchor preference of the top hits. Comparison of ligand binding energies, pharmacokinetic properties with lead compound BX-517 was carried out. Results: Hyrtimomine B, C, D, and G were top hits using iGEMDOCK. The highest score was obtained for hyrtimomine C. Van der Waals interaction at T222 and V96 and hydrogen bond interaction at K111 determined pocket stability. The solubility properties of the compound showed higher score for hyrtimomine C. The conserved features of hyrtimomine C were then compared with the crystal structure of lead compound (BX-517, which was not developed further due to poor solubility and bioavailability). The pharmacokinetic properties of hyrtimomine C were superior to BX-517 and had better solubility and drug-likeness score, hence, may be a candidate structure for drug development. Conclusion: The unique azapeno indole structure of hyrtimomine C highlighted the mode of binding and residues in binding site.

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Design and synthesis of 2-oxindole based multi-targeted inhibitors of PDK1/Akt signaling pathway for the treatment of glioblastoma multiforme

Cited by 42 publications

References 33 publications

Targeting PDK1 for Chemosensitization of Cancer Cells

Targeting PDK1 for Chemosensitization of Cancer Cells

AKT/GSK3β Signaling in Glioblastoma

Molecular Docking of Hyrtimomine a-K From Marine Sponge Hyrtios Spp. As Anticancer Target of Phosphoinositide-Dependent Kinase 1

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