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

• Published in: Acta pharmacologica Sinica 2019-11, Vol.40 (11), p.1436-1447
• Main Authors: Zou, Ling-jiao, Xiang, Qiu-ping, Xue, Xiao-qian, Zhang, Cheng, Li, Chen-chang, Wang, Chao, Li, Qiu, Wang, Rui, Wu, Shuang, Zhou, Yu-lai, Zhang, Yan, Xu, Yong
• Format: Article
• Language: English
• Subjects: Androgen receptors; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Assaying; Biomedical and Life Sciences; Biomedicine; c-Myc protein; Castration; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Proliferation - drug effects; CREB-Binding Protein - chemistry; CREB-Binding Protein - metabolism; Cyclic AMP response element-binding protein; Drug development; E1A-Associated p300 Protein - chemistry; E1A-Associated p300 Protein - metabolism; G1 phase; Homology; Humans; Immunology; Indolizines - pharmacology; Internal Medicine; Invasiveness; Lead compounds; Male; Medical Microbiology; Myc protein; Pharmacology/Toxicology; Prostate cancer; Prostatic Neoplasms - drug therapy; Protein Domains - drug effects; Pyrazoles - pharmacology; Receptors, Androgen - metabolism; Selectivity; Signal Transduction; Tumor cell lines; Vaccine; Wound healing
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0237-5

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 50 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 0 /G 1 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.