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

Authors: Ling-jiao Zou1,2,3, Qiu-ping Xiang1,2,3, Xiao-qian Xue4, Cheng Zhang1,5, Chen-chang Li1, Chao Wang1,2, Qiu Li1,2, Rui Wang1, Shuang Wu1,5, Yu-lai Zhou5, Yan Zhang1,2,3, Yong Xu1,3
1 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510530, China
4 School of Life Science, Huizhou University, Huizhou 516007, China
5 School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China
Correspondence to: Yong Xu:,
DOI: 10.1038/s41401-019-0237-5
Received: 13 December 2018
Accepted: 11 April 2019
Advance online: 16 May 2019


>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.
Keywords: prostate cancer; Y08197; 1-(indolizin-3-yl) ethanone derivative; CBP; EP300; bromodomain inhibitor

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