Newer therapies directed at the full-length (FL) androgen receptor (AR) C-terminal ligand-binding domain
(LBD) such as abiraterone and enzalutamide provide survival benefits to patients with advanced prostate
cancer. Unfortunately, these therapies are not curative. A major mechanism of resistance to these therapies is
the expression of truncated constitutively active AR splice variants (AR-Vs) that lack the LBD. Prostate cancer
patients with metastatic lesions that express AR-Vs should be offered alternative treatments (e.g., taxanes)
instead of inhibitors of FL-AR. Unfortunately, to date there is no technology available that can distinguish which
metastatic lesions express AR-Vs. Circulating tumor cells have many limitations and cannot provide
information about the individual lesions such as whether a specific lesion is responding to therapy while other
lesions may be refractory to the treatment.
The N-terminal domain (NTD) is common to both FL-AR and AR-Vs and is essential for their transcriptional
activities to drive prostate cancer growth. Therefore the intrinsically disordered AR-NTD is a novel therapeutic
target for drug development. We have discovered all of the small molecules such as EPI and sintokamide
(SINT/LPY) that have been proven to directly bind to the AR-NTD and block the transcriptional activities of FL-
AR and AR-Vs. Efficacy of these compounds in preclinical models of castration resistance prostate cancer
(CRPC) led to the clinical development of EPI compounds. EPI-506 showed proof-of-concept in a first-in-
human dose escalation Phase I clinical trial in heavily pre-treated CRPC patients that had failed abiraterone
and/or enzalutamide thereby supporting the approach of targeting the AR-NTD and the EPI scaffold. This was
the first time any drug that directly binds to an intrinsically disordered region reached clinical trials.
Here we assemble leading experts to develop next generation drugs that bind to the intrinsically disordered
AR-NTD as imaging agents and therapeutics for the prognosis and treatment of CRPC. Our short term goal is
to evaluate second generation analogues of EPI-002 (ralaniten) and SINT/LPY that have up to 125-fold better
potency compared to the first generation compounds. This is addressed in Aims 1 and 2 where we will
synthesize novel binders of AR-NTD that have either the EPI or SINT/LYP scaffold and then will characterize
these compounds to select the best candidates for structural analyses (Aim 3), and in Aim 4 for imaging and
efficacy studies. Revealing structural changes will aid in the development of better drugs against this target.
Creation of a molecular imaging agent would potentially provide near-term clinical impact to select patient
treatments based upon expression of AR-Vs in metastatic lesions. Developing drugs that target the AR-NTD to
inhibit both FL-AR and AR-Vs would provide a novel treatment option for these patients.