The androgen receptor (AR) is the best studied drug target for the treatment of prostate cancer. While there are a number of drugs that target the AR, they all work through the same mechanism of action and are prone to the development of drug resistance. There is a large unmet need for novel AR inhibitors which work through alternative mechanism(s). Recent studies have identified a novel site on the AR called Binding Function 3 (BF3) that is involved into AR transcriptional activity. In order to identify inhibitors that target the BF3 site, we have conducted a large-scale in-silico screen followed by experimental evaluation. A number of compounds were identified that effectively inhibited the AR transcriptional activity with no obvious cytotoxicity. The mechanism of action of these compounds was validated by biochemical assays and x-ray crystallography. These findings lay a foundation for the development of alternative or supplementary therapies capable of combating prostate cancer even in its anti-androgen resistant forms.

The androgen receptor (AR) is one of the most studied drug targets for the treatment of prostate cancer. However, all current anti-androgens directly interact with the AR at the androgen binding site, which is prone to resistant mutations, calling for new strategies of the AR inhibition. The current study represents the first attempt to use virtual screening to identify inhibitors of activation function-2 (AF2) of the human AR. By combining large-scale docking with experimental approaches, we were able to identify several small molecules that interact with the AF2 and effectively prevent the transcriptional activation of the AR. The crystallographic structure of one of these inhibitors in complex with the AR provides critical insight into the corresponding protein-ligand interactions and suitable for future hit optimization. Taken together, our results provide a promising ground for development of novel anti-androgens that can help to address the problem of drug resistance in prostate cancer.

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Objective To evaluate the relative incidence of cardiogenic and septic shock in term neonates and identify findings that help differentiate the two entities. Study Design We conducted a retrospective chart review of term neonates presenting to British Columbia Children’s Hospital (BCCH) with decompensated shock of an undiagnosed etiology between January 1, 2008 and January 1, 2013. Charts were reviewed to determine the underlying diagnoses of all neonates meeting our inclusion criteria. Patients were categorized as having septic, cardiogenic, or other etiologies of shock. We then evaluated potential demographic, clinical, and biochemical parameters that could help differentiate between septic and cardiogenic shock. Results Cardiogenic shock was more common than septic shock (relative risk=1.53). A history of cyanosis was suggestive of cardiogenic shock (positive likelihood ratio, LR+=3.2 and negative likelihood ratio, LR−=0.4). Presence of a murmur or gallop (LR+=5.4, LR−=0.3), or decreased femoral pulses (LR+=5.1, LR−=0.5) on physical exam were also suggestive of cardiogenic shock as was cardiomegaly on chest x-ray (LR+=4.9, LR−=0.5). Notably, temperature instability (LR+=0.7, LR−=1.8) and white blood cell count elevation or depression (LR+=0.8, LR−=1.1) were all poor predictors of septic shock. Conclusion Cardiogenic shock is a more common cause of decompensated shock than septic shock. A history of cyanosis, murmur or gallop, or decreased femoral pulses on exam and cardiomegaly on chest x-ray are useful indicators of cardiogenic shock. In evaluating the neonate with decompensated shock, early consideration for Cardiology consultation and interventions to treat the underlying condition is warranted.