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 IC value at 100.67?±?3.30?nM. Y08197 also exhibited high selectivity for CBP/EP300 over other bromodomain-containing proteins. In LNCaP， 22Rv1 and ... More
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 IC 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 G/G 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.
