Constitutively active or oncogenic
forms of Ras are found in ~30% of human cancers and thus represent
an obvious target for drug design. These mutated forms of Ras send
uncontrolled growth signals ultimately leading to malignancies.
The long term objective of this research proposal is to design small
molecules that will interfere with oncogenic Ras binding to its
targets. We have recently discovered two low molecular weight peptides
that significantly inhibit the binding of Ras to its effectors.
We want to understand how these peptides prevent the association
of the Ras/effector complexes. We propose to combine biophysical
and structural techniques to study the complex between Ras and Raf.
First, we want to determine where on Ras the peptides bind by solving
the crystal structure of the Ras/peptide complexes. Second, we want
to determine the affinity constants and the dissociation rates of
the Ras/peptide complex using isothermal titration calorimetry (ITC)
and fluorescence spectroscopy. The structural information generated
from the proposed work will be used to search a combinatorial chemical
library for molecules that mimic the peptides most important features.
These molecules will be later developed into anti cancer drugs. |
