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Dual Inhibition of PDK1 and Aurora Kinase A Page 1 of 36 ACS Chemical Neuroscience 1 2 3 Dual inhibition of PDK1 and Aurora Kinase A: an effective strategy to induce differentiation 4 5 and apoptosis of human glioblastoma multiforme stem cells 6 7 a# a# a a b 8 Simona Daniele , Simona Sestito , Deborah Pietrobono , Chiara Giacomelli , Grazia Chiellini , 9 c d d a* a* 10 Danilo Di Maio , Luciana Marinelli , Ettore Novellino , Claudia Martini , Simona Rapposelli . 11 12 13 14 aDepartment of Pharmacy, University of Pisa, 56126 Pisa, Italy. 15 16 b 17 Department of Pathology, University of Pisa, 56126 Pisa, Italy. 18 c 19 Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy. 20 21 dDepartment of Pharmacy, University of Naples Federico II, Napoli, Italy. 22 23 #These authors contributed equally to this work. 24 25 26 27 *Correspondence and requests for materials should be addressed to C.M. and S.R., Department of 28 Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. E-mail addresses 29 30 [email protected] ; [email protected]. 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 60 ACS Paragon Plus Environment ACS Chemical Neuroscience Page 2 of 36 1 2 3 Abstract 4 5 6 The poor prognosis of Glioblastoma Multiforme (GBM) is mainly attributed to drug resistance 7 8 mechanisms and to the existence of a subpopulation of glioma stem cells (GSCs). Multi-target 9 compounds able to both affect different deregulated pathways and the GSC subpopulation could 10 11 escape tumour resistance, and most importantly, eradicate the stem cell reservoir. 12 13 In this respect, the simultaneous inhibition of Phosphoinositide-dependent kinase-1 (PDK1) and 14 Aurora Kinase A (AurA), each one playing a pivotal role in cellular 15 16 survival/migration/differentiation, could represent an innovative strategy to overcome GBM 17 18 resistance and recurrence. 19 Herein, the cross-talk between these pathways was investigated, using the single-target reference 20 21 compounds MP7 (PDK1 inhibitor) and Alisertib (AurA inhibitor). Furthermore, a new ligand, 22 23 SA16, was identified for its ability to inhibit the PDK1 and the AurA pathways at once, thus 24 proving to be a useful tool for the simultaneous inhibition of the two kinases. SA16 blocked GBM 25 26 cell proliferation, reduced tumour invasiveness, and triggered cellular apoptosis. Most importantly, 27 28 the AurA/PDK1 blocker showed an increased efficacy against GSCs, inducing their differentiation 29 and apoptosis. To the best of our knowledge, this is the first report on combined targeting of PDK1 30 31 and AurA. This drug represents an attractive multi-target lead scaffold for the development of new 32 33 potential treatments for GBM and GSCs. 34 35 36 Key words: Glioblastoma Multiforme; glioma stem cells; phosphoinositide-dependent kinase-1; 37 38 Aurora Kinase A; multi-target compounds. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 60 ACS Paragon Plus Environment Page 3 of 36 ACS Chemical Neuroscience 1 2 3 Introduction 4 5 Glioblastoma (GBM), a grade IV glioma, is a brain tumour displaying a high rate of recurrence and 6 poor prognosis due to its invasive nature 1. Current GBM therapies, including radiation followed by 7 8 the chemotherapeutic agent temozolomide (TMZ), do not yield definitive effects, and the five year 9 2 10 survival rate for GBM is less than 5% in adults . GBM relapse is ascribable to the invasive nature of 11 this tumour, as well as to its resistance to therapy. 3, 4 The incidence of GBM has been related to 12 13 genetic and molecular alterations of different signalling pathways, including the epidermal growth 14 15 factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. In particular, the 3- 16 Phosphoinositide-dependent kinase-1 (PDK1) inhibition has been suggested to block the oncogenic 17 5, 6 18 cellular processes . Moreover, PDK1 phosphorylates and activates Akt, thus playing a pivotal role 19 6 20 in cell survival and tumorigenesis . Overexpression of PDK1 correlates with an aggressive 21 phenotype and poor prognosis 7. Therefore, drugs targeting the PDK1/Akt pathway have emerged as 22 8-10 23 one of the potential treatments for GBM . However, specific target drugs, including those against 24 11 25 PDK1, did not show a significant clinical efficacy , and preclinical studies on PDK1 inhibitors 26 have been hampered by the lack of peculiar proof-of-concept molecules 5,12-14 . In fact, canonical 27 28 drug resistance processes include an increased expression of efflux pumps, drug target alterations, 29 15 16, 17 30 over-activation of pro-survival pathways , and most important, clonal heterogeneity . 31 Recently, GBM recurrence and resistance to therapies have also been related to the presence of 32 33 GBM stem-like cells (GSCs), a sub-population of multipotent tumour-initiating cells displaying 34 18, 19 35 stem cell-like characteristics . Aggressiveness and unresponsiveness of gliomas have been 36 correlated with the number of GSCs 3, and long-term temozolomide (TMZ) treatment has been 37 20 38 shown to favour the emergence of drug-resistant GBM cells , indicating that a stem cell-oriented 39 40 therapy is needed to prevent GBM recurrence and to improve the outcome of treatments. 41 Eradication of the GSC reservoir, by blockade of key pathways involved in stem cell maintenance, 42 43 has been found to effectively reduce their tumorigenic potential 21, 22 . Among these pathways, the 44 45 Aurora kinase A (AurA) has emerged as an effective target. AurA is a serine–threonine kinase that 46 plays a pivotal role in cellular proliferation and differentiation of several tumours, including GBM 23, 47 48 24 . In particular, AurA is expressed in gliomas and is associated with patient survival, thus 49 25 50 representing a potential therapeutic target for GBM . More important, blocking the AurA pathway 51 resulted in inhibition of GSC colony formation and potentiation of the common GBM 52 53 chemotherapeutics 23 . On the basis of these considerations, a multi-target approach 16 that is able to 54 55 impact multiple deregulated and escape pathways, and deplete the GSC reservoir, may offer the 56 most promising strategy for the treatment of GBM and minimize drug resistance. Among these 57 58 59 3 60 ACS Paragon Plus Environment ACS Chemical Neuroscience Page 4 of 36 1 2 3 approaches, the simultaneous disruption of PDK1 and AurA, each one playing a pivotal role in the 4 5 cellular survival/migration/differentiation, could represent an innovative strategy to overcome GBM 6 resistance and recurrence. In this respect, a few compounds, classified as PDK1 inhibitors, have 7 8 been shown to also affect AurA activity. For instance, OSU-03012, a PDK1 inhibitor, was found to 9 26 10 affect multiple cellular targets, including the AurA one, in neuroblastoma and other cancer cells , 11 thus supporting the aforementioned mechanistic rationale (Fig. 1). 12 13 Herein, the molecular mechanisms at the basis of a simultaneous PDK1/AurA inhibition were 14 15 explored in different GBM cell lines, as well as in a GBM-derived stem-like culture. As a first step, 16 the standard PDK1 inhibitor, MP7 12 , and the AurA blocker Alisertib (MLN8237) 23 were used as 17 18 reference compounds to investigate the functional crosstalk between the two pathways in GBM. 19 20 Furthermore, starting from previously synthesized PDK1 inhibitors, namely OXID-pyridonyl 21 hybrids 9, 10 , we identified SA16 as a new ligand able to inhibit both the PDK1 and the AurA 22 23 pathways at once and thus useful in establishing the preclinical proof of mechanism for the 24 25 simultaneous inhibition of these two pathways (Fig. 1). The new identified compound decreased 26 GBM cell proliferation, triggered cellular apoptosis and reduced cell invasiveness. Moreover, this 27 28 novel AurA/PDK1 blocker showed a marked efficacy on GSCs by inducing differentiation and 29 30 apoptosis. 31 To the best of our knowledge, this is the first study reporting a combinatorial treatment strategy 32 33 based on the simultaneous inhibition of PDK1 and AurA. Furthermore, we identified an innovative 34 35 PDK1/AurA dual-target molecule which could represent an attractive lead scaffold for the design 36 and synthesis of new multi-target treatments for GBM and, most importantly, for GSCs. 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 4 60 ACS Paragon Plus Environment Page 5 of 36 ACS Chemical Neuroscience 1 2 3 Results and Discussion 4 5 The combined inhibition of PDK1 and AurA affects GBM cell proliferation. 6 In order to study the combined effects of PDK1 and AurA inhibition, the U87MG cells were chosen 7 8 as representative GBM cell line, since they are characterised by: i) the lack of the tumour 9 27, 28 10 suppressor phosphatase and tensin homologue (PTEN), a negative regulator of the Akt pathway , 11 and ii) the expression of a functional AurA 25 . 12 13 First, we assessed the effects on adherent U87MG cell proliferation following combined inhibition 14 15 of the two kinases. The experiments were performed in the presence of the PDK1 inhibitor MP7, 16 alone or in combination with the AurA inhibitor, Alisertib. These reference compounds were used 17 29, 30 18 starting from a concentration corresponding to the IC 50 value on the target kinases . 19 20 Following 72 h treatment, MP7 alone did not show a significant inhibition of GBM proliferation 21 (Fig.
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