1 research outputs found
Identification of the First Inhibitor of the GBP1:PIM1 Interaction. Implications for the Development of a New Class of Anticancer Agents against Paclitaxel Resistant Cancer Cells
Class
III β-tubulin plays a prominent role in the development of drug
resistance to paclitaxel by allowing the incorporation of the GBP1
GTPase into microtubules. Once in the cytoskeleton, GBP1 binds to
prosurvival kinases such as PIM1 and initiates a signaling pathway
that induces resistance to paclitaxel. Therefore, the inhibition of
the GBP1:PIM1 interaction could potentially revert resistance to paclitaxel.
A panel of 44 4-azapodophyllotoxin derivatives was screened in the
NCI-60 cell panel. The result is that 31 are active and the comparative
analysis demonstrated specific activity in paclitaxel-resistant cells.
Using surface plasmon resonance, we were able to prove that NSC756093
is a potent in vitro inhibitor of the GBP1:PIM1 interaction and that
this property is maintained in vivo in ovarian cancer cells resistant
to paclitaxel. Through bioinformatics, molecular modeling, and mutagenesis
studies, we identified the putative NSC756093 binding site at the
interface between the helical and the LG domain of GBP1. According
to our results by binding to this site, the NSC756093 compound is
able to stabilize a conformation of GBP1 not suitable for binding
to PIM1