The proto-oncogene Bcl-3 is a co-factor for the transcription factor
NF-kB, regulating NF-kB dependent gene expression through
direct protein-protein interaction with the subunits, p50 and p52.
Consequently it modulates both canonical and alternative NF-kB
pathways responsible for a variety of cellular functions in normal
and pathological settings.
Loss of Bcl3 expression resulted in an 80% reduction in
metastatic tumour burden, with no overt detriment to normal
tissue homeostasis. Suppression of Bcl3 interaction with p50/p52
using a protein-binding mutant of Bcl3 replicated this phenotype in
human breast cancer xenografts in vivo, an outcome linked to a
reduction in cell motility in vitro.
Molecular modeling of the Bcl-3 complexes with p50 and p52, and
a subsequent in silico screening of a compound library against a
specific site on Bcl-3 resulted in the identification of a nM efficient
inhibitor that modulated NF-kB signaling and reduced cell motility
in vitro. Use of this compound in mouse models of metastatic
breast cancer resulted in a dramatic reduction in metastatic
tumour burden. Based on these results, it is possible to say that
this novel class of compounds show real promise as putative anticancer
agents.
12/06/2023
Aula A Giuliano Dip Chimica e Tecnologia del Farmaco CU019 11.00-12.00