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Ref Type Journal Article
PMID (27797168)
Authors Daniele S, Sestito S, Pietrobono D, Giacomelli C, Chiellini G, Di Maio D, Marinelli L, Novellino E, Martini C, Rapposelli S
Title Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells.
Journal ACS chemical neuroscience
Vol 8
Issue 1
Date 2017 Jan 18
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MP7 MP7 1 0
SA16 SA16 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MP7 PDPK1 Inhibitor 10 MP7 is an inhibitor of phophoinostodine-dependent kinase (PDPK1), which, when combined with other agents, may result in inhibition of cell proliferation and reduced viability of cancer cells (PMID: 27797168).
SA16 Aurka Inhibitors 23 PDPK1 Inhibitor 10 SA16 is a dual inhibitor of phosphoinositide-dependent kinase-1 (PDPK1) and AURKA, which may result in cell proliferation blockade and induction of apoptosis (PMID: 27797168).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown glioblastoma multiforme no benefit MP7 Preclinical - Cell culture Actionable In a preclinical study, MP7 treatment did not result in significant inhibition of cell proliferation and showed minimal change in cell viability in a glioblastoma cell line in culture, thus, providing no benefit (PMID: 27797168). 27797168
Unknown unknown glioblastoma multiforme not applicable SA16 Preclinical - Cell culture Actionable In a preclinical study, SA16 treatment in glioblastoma cells resulted in decreased cell proliferation, reduced cell viability, and apoptotic induction in culture, and inhibited glioma stem cell formation (PMID: 27797168). 27797168
Unknown unknown glioblastoma multiforme not applicable Alisertib + MP7 Preclinical - Cell culture Actionable In a preclinical study, the combination of MP7 and Alisertib (MLN8237) resulted in an additive effect in glioblastoma cells in culture, demonstrating an increase in antiproliferative activity, decreased cell viability, and inhibition of glioma stem cell colony formation (PMID: 27797168). 27797168