Inducible Degradation of Oncogenic Nucleolin Using an Aptamer-Based PROTAC

While proteolysis-targeting chimeras (PROTACs) are showing
promise
for targeting previously undruggable molecules, their application
has been limited by difficulties in identifying suitable ligands and
undesired on-target toxicity. Aptamers can virtually recognize any
protein through their unique and switchable conformations. Here, by
exploiting aptamers as targeting warheads, we developed a novel strategy
for inducible degradation of undruggable proteins. As a proof of concept,
we chose oncogenic nucleolin (NCL) as the target and generated a series
of NCL degraders, and demonstrated that dNCL#T1 induced NCL degradation
in a ubiquitin-proteasome-dependent manner, thereby inhibiting NCL-mediated
breast cancer cell proliferation. To reduce on-target toxicity, we
further developed a light-controllable PROTAC, opto-dNCL#T1, by introducing
a photolabile complementary oligonucleotide to hybridize with dNCL#T1.
UVA irradiation liberated dNCL#T1 from caged opto-dNCL#T1, leading
to dNCL#T1 activation and NCL degradation. These results indicate
that aptamer-based PROTACs are a viable alternative approach to degrade
proteins of interest in a highly tunable manner.