Y08197 is a novel and selective CBP/EP300 bromodomain inhibitor for the treatment of prostate cancer

摘要

In advanced prostate cancer,CREB (cAMP-responsive element-binding protein) binding protein (CBP) and its homolog EP300 are highly expressed;targeting the bromodomain of CBP is a new strategy for the treatment of prostate cancer.In the current study we identified Y08197,a novel 1-(indolizin-3-yl) ethanone derivative,as a selective inhibitor of CBP/EP300 bromodomain and explored its antitumor activity against prostate cancer cell lines in vitro.In the AlphaScreen assay,we demonstrated that Y08197 dose-dependently inhibited the CBP bromodomain with an IC50 value at 100.67 ± 3.30 nM.Y08197 also exhibited high selectivity for CBP/EP300 over other bromodomain-containing proteins.In LNCaP,22Rv1 and VCaP prostate cancer cells,treatment with Y08197 (1,5 μM) strongly affected downstream signaling transduction,thus markedly inhibiting the expression of androgen receptor (AR)-regulated genes PSA,KLK2,TMPRSS2,and oncogenes C-MYC and ERG.Notably,Y08197 potently inhibited cell growth in several AR-positive prostate cancer cell lines including LNCaP,22Rv1,VCaP,and C4-2B.In 22Rv1 prostate cancer cells,treatment with Y08197 (1,4,16 μM) dose-dependently induced G0/G1 phase arrest and apoptosis.Furthermore,treatment with Y08197 (5 μM) significantly decreased ERG-induced invasive capacity of 22Rv1 prostate cancer cells detected in wound-healing assay and cell migration assay.Taken together,CBP/EP300 inhibitor Y08197 represents a promising lead compound for development as new therapeutics for the treatment of castration-resistant prostate cancer.