化学
体内
药理学
细胞毒性
雌激素受体
原癌基因酪氨酸蛋白激酶Src
药代动力学
癌细胞
转移
体外
癌症研究
癌症
受体
生物化学
乳腺癌
生物
内科学
医学
生物技术
作者
Dong Lu,Jianwei Chen,Li Qin,Imani Bijou,Ping Yi,Feng Li,Xianzhou Song,Kevin R. MacKenzie,Xiaofeng Yu,Bin Yang,Sandipan Chowdhury,James D. Korp,Bert W. O’Malley,David M. Lonard,Jin Wang
标识
DOI:10.1021/acs.jmedchem.3c01596
摘要
Steroid receptor coactivator 3 (SRC-3) is a critical mediator of many intracellular signaling pathways that are crucial for cancer proliferation and metastasis. In this study, we performed structure-activity relationship exploration and drug-like optimization of the hit compound SI-2, guided by in vitro/in vivo metabolism studies and cytotoxicity assays. Our efforts led to the discovery of two lead compounds, SI-10 and SI-12. Both compounds exhibit potent cytotoxicity against a panel of human cancer cell lines and demonstrate acceptable pharmacokinetic properties. A biotinylated estrogen response element pull-down assay demonstrated that SI-12 could disrupt the recruitment of SRC-3 and p300 in the estrogen receptor complex. Importantly, SI-10 and SI-12 significantly inhibited tumor growth and metastasis in vivo without appreciable acute toxicity. These results demonstrate the potential of SI-10 and SI-12 as drug candidates for cancer therapy, given their potent SRC-3 inhibition and promising pharmacokinetic and toxicity profiles.
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