Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

Gankyrin is an oncoprotein responsible
for the development of numerous
cancer types. It regulates the expression levels of multiple tumor
suppressor proteins (TSPs) in liver cancer; however, gankyrin’s
regulation of these TSPs in breast and lung cancers has not been thoroughly
investigated. Additionally, no small-molecule gankyrin inhibitor has
been developed which demonstrates potent anti-proliferative activity
against gankyrin overexpressing breast and lung cancers. Herein, we
are reporting the structure-based design of gankyrin-binding small
molecules which potently inhibited the proliferation of gankyrin overexpressing
A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited
the growth of 3D spheroids in an in vitro tumor simulation
model. Investigations demonstrated that gankyrin inhibition occurs
through either stabilization or destabilization of its 3D structure.
These studies shed light on the mechanism of small-molecule inhibition
of gankyrin and demonstrate that gankyrin is a viable therapeutic
target for the treatment of breast and lung cancer.