Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands

Androgen receptor (AR) is a validated therapeutic target
for the
treatment of metastatic castration-resistant prostate cancer (mCRPC).
We report herein our design, synthesis, and biological characterization
of highly potent small-molecule proteolysis targeting chimera (PROTAC)
AR degraders using a potent AR antagonist and E3 ligase ligands with
weak binding affinities to VHL protein. Our study resulted in the
discovery of 11 (ARD-266), which effectively induces
degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1
prostate cancer cell lines with DC50 values of 0.2–1
nM. ARD-266 is capable of reducing the AR protein level by >95%
in
these AR+ prostate cancer cell lines and effectively reduces AR-regulated
gene expression suppression. For the first time, we demonstrated that
an E3 ligand with micromolar binding affinity to its E3 ligase complex
can be successfully employed for the design of highly potent and efficient
PROTAC degraders and this finding may have a significant implication
for the field of PROTAC research.