< Back to previous page

Project

Structural, molecular, and cellular biology of PKD2 allosteric modulators as novel therapeutics for cancer

Recently, we applied computer aided drug design to develop
allosteric, isoenzyme specific inhibitors of Protein Kinase D2 (PKD2).
We have now validated our compounds as truly PKD2 isoenzyme
specific, with promising properties against pancreatic cancer,
glioblastoma and multiple myeloma (cancers of high unmet medical
need). While we have designed the compounds to bind a specific
location in PKD2, the crystal structure revealing the interactions on
the atomic level is not yet solved. Hence, for rational design of
improved inhibitors, we will solve the structure of the Allstars in
complex with their receptor. This will allow rational design of novel
chemotypes as lead compounds for the future development of a
second generation of Allstar compounds.
The further development of Allstar molecules will occur in iterative
cycles of in silico design > purchase or synthesis > enzymatic and
cellular testing. The enzymatic and cellular testing provides insights,
not only for the further refinement of the Allstars, but also on how
PKD2 is involved in various cancer hallmarks. Furthermore, the most
promising Allstars, will be analysed for their effect on tumor biology
via 1) advanced in vivo imaging in mouse models, 2) single cell RNA
sequencing for their effect on signaling pathways, and 3) multiplex
protein staining for next generation pathology of tumor specimens
generating insights on molecular and pathophysiological processes
affected by the Allstars in tumors.

Date:1 Jan 2022 →  Today
Keywords:computer aided drug design, protein kinases, allosteric stabilisation
Disciplines:Small molecules, Cell signalling, (Bio)molecular modelling and design, Drug discovery and development not elsewhere classified, Structural biology