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Open AccessArticle

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

1
Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley 6102, Australia
2
Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy
3
Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University “G. d’Annunzio” di Chieti-Pescara, Center for Advanced Studies and Technology (CAST), 66100 Chieti, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(11), 1695; https://doi.org/10.3390/cancers11111695
Received: 8 October 2019 / Revised: 26 October 2019 / Accepted: 28 October 2019 / Published: 31 October 2019
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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. View Full-Text
Keywords: 3-phosphoinositide-dependent protein kinase 1; aurora kinase; PDK1/aurora A inhibitor; dual inhibitor; pancreatic cancer; cell proliferation; cell migration 3-phosphoinositide-dependent protein kinase 1; aurora kinase; PDK1/aurora A inhibitor; dual inhibitor; pancreatic cancer; cell proliferation; cell migration
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Casari, I.; Domenichini, A.; Sestito, S.; Capone, E.; Sala, G.; Rapposelli, S.; Falasca, M. Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation. Cancers 2019, 11, 1695.

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