Lab review: Molecular dissection of the signal transduction pathways associated with PTEN deletion-induced optic nerve regeneration
RESTORATIVE NEUROLOGY AND NEUROSCIENCE
Authors: Huang, Haoliang; Kaur, Simran; Hu, Yang
Abstract
Background: Permanent loss of vital functions after central nervous system (CNS) injury occurs in part because axons in the adult mammalian CNS do not regenerate after injury. PTEN was identified as a prominent intrinsic inhibitor of CNS axon regeneration about 10 years ago. The PTEN negatively regulated PI3K-AKT-mTOR pathway, which has been intensively explored in diverse models of axon injury and diseases and its mechanism for axon regeneration is becoming clearer. Objective: It is timely to summarize current knowledge about the PTEN/AKT/mTOR pathway and discuss future directions of translational regenerative research for neural injury and neurodegenerative diseases. Methods: Using mouse optic nerve crush as an in vivo retinal ganglion cell axon injury model, we have conducted an extensive molecular dissection of the PI3K-AKT-mTORC1/mTORC2 pathway to illuminate the cross-regulating mechanisms in axon regeneration. Results: AKT is the nodal point that coordinates both positive (PI3K-PDK1-pAKT-T308) and negative (PI3K-mTORC2-pAKT-S473) signals to regulate adult CNS axon regeneration through two parallel pathways, activating mTORC1 and inhibiting GSK3 beta. However, mTORC1/S6K1-mediated feedback inhibition after PTEN deletion prevents potent AKT activation. Conclusions: A key permissive signal from an unidentified AKT-independent pathway is required for stimulating the neuron-intrinsic growth machinery. Future studies into this complex neuron-intrinsic balancing mechanism involving necessary and permissive signals for axon regeneration is likely to lead to safe and effective regenerative strategies for CNS repair.
Design, synthesis, crystal structures and anticancer activity of 4-substituted quinolines to target PDK1
BIOORGANIC CHEMISTRY
Authors: Vennila, K. N.; Sunny, D.; Madhuri, S.; Ciattini, Samuele; Chelazzi, Laura; Elango, Kuppanagounder P.
Abstract
The induced fit docking of anilino quinoline scaffold results in the required hydrogen bonding interactions with amino acid residues in the orthosteric site of 3 Phosphoinositide dependent kinase (PDK1). The rational design of 4-substituted amino quinolines is carried out and eight compounds are synthesized. Four crystal structures are determined and their binding mode with adenosine triphosphate (ATP) site of PDK1 is analyzed. The anticancer activity in A549 cell lines of the test compounds by MTT assay resulted in an inhibitor with IC50 value of 0.96 mu M which is less than the pemetrexed, a marketed lung cancer drug.
COA
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