Development of Phage Assisted Continuous Evolution of the Human Androgen Receptor
Abstract
Prostate cancer (PC) is the second leading cause of male cancer-related
deaths in the United States. The central molecule in the development and
progression of PC is the androgen receptor (AR), which serves as the most
therapeutically relevant target for chemoprevention and drug therapy. First
generation AR antagonists, such as bicalutamide and flutamide, exhibit only
partial receptor antagonism prompting continued cancer proliferation and
metastasis. Thus, the development of more powerful AR antagonists that
exhibit pure antagonistic activities would prove to be of great therapeutic
value. Unfortunately, despite more than 20 years of crystallization effort
focused on the AR, a ligand binding domain (ARlbd) antagonist bound
crystal structure remains elusive due to poor expression and and an
inherently low protein solubility. In this study we propose a system using
phage assisted continuous evolution (PACE; Figure 1.), a novel technique
for directed evolution, to overcome the inherently low soubility exhibited by
ARlbd to aid in ongoing crystallization efforts.