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

ABSTRACT: 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??M) 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??M) dose-dependently induced G0/G1 phase arrest and apoptosis. Furthermore, treatment with Y08197 (5??M) 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.

SUBMITTER: Zou LJ

PROVIDER: S-EPMC6889168 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Zou Ling-Jiao LJ Xiang Qiu-Ping QP Xue Xiao-Qian XQ Zhang Cheng C Li Chen-Chang CC Wang Chao C Li Qiu Q Wang Rui R Wu Shuang S Zhou Yu-Lai YL Zhang Yan Y Xu Yong Y

Acta pharmacologica Sinica 20190516 11

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 ...[more]

PMID: 31097763

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Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.

Dataset Information

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

Publications

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

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