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Locking PDK1 in DFG-out conformation through 2-oxo-indole containing molecules: Another tools to fight glioblastoma
Simona Sestito1, Simona Daniele1, Giulia Nesi1
1Department of Pharmacy, University of Pisa, Via Bonanno, 6, 56126 Pisa, Italy.
Abstract:
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 = 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.
Insights
Researchers designed novel phosphoinositide-dependent kinase-1 (PDK1) inhibitors by merging molecular fragments. Compound 8 emerged as a promising lead candidate for a new generation of PDK1-targeted cancer therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Phosphoinositide-dependent kinase-1 (PDK1) is a key regulator in the PI3K/Akt pathway, crucial for cell proliferation, survival, and metastasis.
- PDK1's role in tumorigenesis makes it a significant therapeutic target, yet no PDK1 inhibitors have reached clinical application.
- Existing efforts to develop PDK1 inhibitors have not yet yielded clinically approved drugs.
Purpose of the Study:
- To design and synthesize novel, potent inhibitors targeting PDK1.
- To explore a new class of molecules by combining 2-oxo-indole and 2-oxo-pyridonyl fragments.
- To identify lead compounds for a new generation of PDK1-targeted cancer therapies.
Main Methods:
- Design and synthesis of novel hybrid molecules integrating 2-oxo-indole and 2-oxo-pyridonyl moieties.
- Computational analysis using molecular docking and Molecular Dynamics (MD) simulations to understand binding modes.
- In vitro evaluation of the most potent compound (hybrid 8) for kinase inhibition, cytotoxicity, and anti-migratory effects.
Main Results:
- A series of novel hybrid molecules targeting PDK1 were synthesized.
- Molecular modeling provided insights into the binding interactions of the designed compounds.
- Hybrid 8 demonstrated significant PDK1 inhibition (IC50 = 112 nM) and reduced tumor cell migration in vitro.
Conclusions:
- The designed OXID-pyridonyl hybrids represent a promising new class of PDK1 inhibitors.
- Compound 8 is identified as a lead compound for further development in PDK1-targeted cancer therapy.
- These findings encourage continued research into this novel class of kinase inhibitors.
