PDK1 inhibitor is a potent and selective inhibitor of PDK1 with potential as anticancer agent with IC50 of 1 nM, displays >3,000-fold selectivity against a panel of 256 kinases; specifically inhibits cellular PDK1 T-loop phosphorylation (Ser-241), inhibits p-RSK S221 in PC-3 cells with EC50 of 300 nM, inhibits colony formation in a subset of cancer cell lines (4 of 10) and primary xenograft tumor lines (9 of 57).
1. ACS Chem Neurosci. 2017 Jan 18;8(1):100-114. doi: 10.1021/acschemneuro.6b00251.
Epub 2016 Nov 10.
Dual Inhibition of PDK1 and Aurora Kinase A: An Effective Strategy to Induce
Differentiation and Apoptosis of Human Glioblastoma Multiforme Stem Cells.
Daniele S, Sestito S, Pietrobono D, Giacomelli C, Chiellini G, Di Maio D(1),
Marinelli L(2), Novellino E(2), Martini C, Rapposelli S.
(1)Scuola Normale Superiore , Piazza dei Cavalieri 7, I-56126 Pisa, Italy.
(2)Department of Pharmacy, University of Naples Federico II , Napoli, Italy.
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.