A Novel Compound QW07 Targets Androgen Receptor To Suppress Castration Resistant Prostate Cancer

Prostate cancer is one of the most common malignancies in males of developed countries.With the change of dietary structure and the aging of population,the morbidity and mortality rate are increasing year by year.Prostate cancer is a hormone-driven tumor depends on the androgen receptor(AR)signaling pathway.Clinically,androgen deprivation therapy is the most common treatment strategy for advanced prostate cancer,but majority of patients will recur to castration resistant prostate cancer(CRPC)and progress without the existence of androgen.The molecular mechanism research show that the continuous activation of AR signaling pathway is the main reason of prostate cancer progressing to CRPC,especially the non-specific ligand activation and ligand-independent activation of AR.Enzalutamide(an antagonist of AR-LBD)and abiraterone(inhibitting the synthesis of endogenous androgen)targetting AR signal pathway have been approved for the treatment of CRPC by FDA.These drugs bring some benefit to patients in clinical,but the overall benefit is still very limited.The reason is that both drugs can only inhibit AR-LBD-dependent activation rather than AR-NTD activation.Thus,next new generation antagonist targeting the transcriptional activity of AR-NTD is an important approach for the treatment of CRPC.In order to screen and identify small molecule compound that specifically inhibit AR-NTD transcriptional activity,we constructed a high-throughput screening system targeting AR-NTD transcription activity.We carried out on a small molecule library containing more than 1,000 compounds and got a novel compound QW07,which specifically inhibits AR-NTD transcriptional activity and the specific inhibitory activity was verified in a number of subsequent models in which shown better activity than positive compound EPI001.Further studies shown that QW07 binding directly to AR-NTD and blocking the interaction of co-regulatory proteins such as CBP with AR-NTD,which results expression inhibition of downstream genes by inhibiting the formation of AR transcription complex and blocking the interaction of AR and androgen response elements(AREs).In cell lines,QW07 showed a more sensitivity inhibition of AR-positive prostate cancer cells and inhibited clonal formation at low concentrations.QW07 also inhibited the growth of CRPC tumors in multiple models while showed acceptable toxicity.In summary,the novel small molecule compound QW07 is expected to be a candidate compound targeting AR-NTD for the treatment of CRPC.