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In 2018, the overall number of new cases of prostate cancer in the United States is
predicted to be 164, 690, making prostate cancer a major contributor to overall cancer incidence,
second only to that of the lung.1
Currently, androgen deprivation therapy (ADT) is the standard of care for advanced and
metastatic prostate cancer.2,3 ADT consists of either surgical castration or, more commonly,
chemical castration, via the direct inhibition of the AR or the inhibition of substrate biosynthesis,
via estrogen therapy or GnRH agonists.4 This treatment option is effective for a median period of
2-3 years before promoting a state of castration-resistant prostate cancer (CRPC).3 CPRC,
defined as acquiring resistance to chemical or surgical ADT, will arise in almost all cases. It
remains largely incurable3 despite the use of docetaxel-based chemotherapy5,6 or second
generation AR-inhibitors3 as subsequent treatment options.
Though resistant to ADT, CRPC has been shown to rely on the androgen receptor (AR),
which remains a realistic therapeutic target.2,3,5 The androgen receptor includes the N-terminal
domain (NTD), the DNA-binding domain, the hinge region, and C-terminal domain, housing the
ligand-binding domain (LBD), spanning its 9 exons.2,3,7 Clinically relevant second generation
AR inhibitors include enzalutamide and abiraterone acetate, which work to block LBD function
via either direct or substrate biosynthesis inhibition, respectively.3 Though resistance to these
treatments ultimately occurs via the creation of LBD-deficient or mutated AR variants, which
have been associated with driving CRPC progression, the initial efficacy of these treatments
validate the role of the AR in CRPC progression.7 Thus, AR-targeted therapeutics remain
relevant in drug development.
Notably, the NTD of the AR remains appealing as a therapeutic target because of its
presence in most known AR splice variants,7 potentially bypassing the alternative splicing
mechanism of resistance. In addition to this, the role of the NTD in AR nuclear localization7,8
and its binding of co-regulatory molecules3,9 add to its importance in AR function. Currently, no
therapeutic in clinical use exists that targets the NTD of the AR. Thus, we hypothesize small
molecule-driven inhibition of the NTD on the AR will reduce viability of in vitro AR-positive,
androgen dependent and independent prostate cancer cells.

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