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p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 12.0px Helvetica}span.s1 {font: 8.0px Helvetica}In 2018, the overall number of new cases of prostate cancer in the United States ispredicted to be 164, 690, making prostate cancer a major contributor to overall cancer incidence,second only to that of the lung.

1Currently, androgen deprivation therapy (ADT) is the standard of care for advanced andmetastatic 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 of2-3 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. Itremains largely incurable3 despite the use of docetaxel-based chemotherapy5,6 or secondgeneration 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-terminaldomain (NTD), the DNA-binding domain, the hinge region, and C-terminal domain, housing theligand-binding domain (LBD), spanning its 9 exons.2,3,7 Clinically relevant second generationAR inhibitors include enzalutamide and abiraterone acetate, which work to block LBD functionvia either direct or substrate biosynthesis inhibition, respectively.3 Though resistance to thesetreatments ultimately occurs via the creation of LBD-deficient or mutated AR variants, whichhave been associated with driving CRPC progression, the initial efficacy of these treatmentsvalidate the role of the AR in CRPC progression.7 Thus, AR-targeted therapeutics remainrelevant in drug development.Notably, the NTD of the AR remains appealing as a therapeutic target because of itspresence in most known AR splice variants,7 potentially bypassing the alternative splicingmechanism of resistance. In addition to this, the role of the NTD in AR nuclear localization7,8and its binding of co-regulatory molecules3,9 add to its importance in AR function.

Currently, notherapeutic in clinical use exists that targets the NTD of the AR. Thus, we hypothesize smallmolecule-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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