Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma

The phosphoinositide-dependent kinase-1 (PDK1) is one of the main components of the PI3K/Akt
pathway. Also named the “master kinase” of the AGC family, PDK1 plays a critical role in tumorigenesis,
by enhancing cell proliferation and inhibiting apoptosis, as well as in cell invasion and metastasis formation.
Although there have been done huge efforts in discovering specific compounds targeting PDK1,
nowadays no PDK1 inhibitor has yet entered the clinic. With the aim to pick out novel and potent PDK1
inhibitors, herein we report the design and synthesis of a new class of molecules obtained by merging
the 2-oxo-indole nucleus with the 2-oxo-pyridonyl fragment, two moieties with high affinity for the
PDK1 hinge region and its DFG-out binding site, respectively. To this purpose, a small series of compounds
were synthesised and a tandem application of docking and Molecular Dynamic (MD) was
employed to get insight into their mode of binding. The OXID-pyridonyl hybrid 8, possessing the lower
IC50 (IC50 ¼ 112 nM), was also tested against recombinant kinases involved in the PI3K/PDK1/Akt
pathway and was subjected to vitro studies to evaluate the cytotoxicity and the inhibition of tumour cell
migration. All together the results let us to consider 8, as a lead compound of a new generation of PDK1
inhibitors and encourage us to further studies in this direction.