Abstract
The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 542-559 |
| Number of pages | 18 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 152 |
| DOIs | |
| State | Published - May 25 2018 |
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Keywords
- 3,5-Dimethylisoxazole
- BRD4
- Bromodomain inhibitor
- Prostate cancer
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
Cite this
Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer. / Xue, Xiaoqian; Zhang, Yan; Wang, Chao; Zhang, Maofeng; Xiang, Qiuping; Wang, Junjian; Wang, Anhui; Li, Chenchang; Zhang, Cheng; Zou, Lingjiao; Wang, Rui; Wu, Shuang; Lu, Yongzhi; Chen, Hongwu; Ding, Ke; Li, Guohui; Xu, Yong.
In: European Journal of Medicinal Chemistry, Vol. 152, 25.05.2018, p. 542-559.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
AU - Xue, Xiaoqian
AU - Zhang, Yan
AU - Wang, Chao
AU - Zhang, Maofeng
AU - Xiang, Qiuping
AU - Wang, Junjian
AU - Wang, Anhui
AU - Li, Chenchang
AU - Zhang, Cheng
AU - Zou, Lingjiao
AU - Wang, Rui
AU - Wu, Shuang
AU - Lu, Yongzhi
AU - Chen, Hongwu
AU - Ding, Ke
AU - Li, Guohui
AU - Xu, Yong
PY - 2018/5/25
Y1 - 2018/5/25
N2 - The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
AB - The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
KW - 3,5-Dimethylisoxazole
KW - BRD4
KW - Bromodomain inhibitor
KW - Prostate cancer
UR - http://www.scopus.com/inward/record.url?scp=85047016155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047016155&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.04.034
DO - 10.1016/j.ejmech.2018.04.034
M3 - Article
C2 - 29758518
AN - SCOPUS:85047016155
VL - 152
SP - 542
EP - 559
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -