Discovery of novel kinase inhibitors for neurodegeneration

Context

As a research leader at the Institute for Molecular Bioscience (University of Queensland), I led a collaborative project to identify new small-molecule inhibitors for kinases implicated in Alzheimer’s disease, including CDK5 and GSK3β.

Client/Partner Type

Academic–Industry Collaboration (Supported by ARC and Noscira S.A.).

Challenge

Effective treatments for neurodegenerative diseases are limited. The kinases CDK5 and GSK3β play key roles in tau hyperphosphorylation and are validated targets in Alzheimer’s. The challenge was rapidly identifying potent and selective kinase inhibitors from underexplored marine biodiversity.

Solution

We screened 2,600+ marine extracts and conducted virtual screening of 1,500+ marine-derived metabolites using the GOLD docking engine against the ATP-binding site of CDK5. I led the molecular modelling, docking, and structure–activity prioritization pipeline, integrating it with kinase assays (in partnership with Noscira S.A.) to identify hits.

Outcome

• Discovered novel scaffolds with submicromolar activity against CDK5, CK1δ, and GSK3β.

• Co-authored four peer-reviewed articles, including one with mechanistic insights;

  Plisson, F.; Conte, M.; Khalil, Z.; Huang, X.-C.; Piggott A. M. & Capon, R. J.*. Kinase inhibitor scaffolds against neurodegenerative disorders from a southern Australian ascidian, Didemnum sp. ChemMedChem 2012, 7(6), 980-993. [DOI]

• Contributed to a granted patent covering these novel kinase inhibitor scaffolds.

  Therapeutic use of indole-dihydro-imidazole derivatives WO2013167635

  
  

Tools

GOLD (docking suite), ligand preparation (ChemDraw), molecular modelling (Sybyl, Omega, PyMOL), and kinase assays.

N.B. This workflow laid the groundwork for Ingenie Bio's current virtual screening and small-molecule discovery services.