Jiang Fen, Guo An-Ping, Xu Jia-Cheng, Wang Hui-Jie, Mo Xiao-Fei, You Qi-Dong, Xu Xiao-Li
State Key Laboratory of Natural Medicines, And Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of Natural Medicines, And Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Eur J Med Chem. 2017 Dec 1;141:1-14. doi: 10.1016/j.ejmech.2017.07.080. Epub 2017 Aug 2.
In order to discover novel Hsp90 inhibitors targeting the C-terminal ATP binding pocket, a novobiocin derivative based ROCS model was constructed for virtual screening. Compound 13 was identified as the lead compound and then systematical structure activity relationship (SAR) study was conducted. These efforts led to compound 69, which exhibited potent anti-proliferative activities against MCF7 and SKBr3 breast cancer cell lines. In 4T1 mice breast cancer models, 69 exhibited potent tumor growth inhibition and anti-metastasis effect. Compound 69 as a potent antitumor agent targeting the Hsp90 C-terminal is worthy of further pre-clinical study.
为了发现靶向C端ATP结合口袋的新型Hsp90抑制剂，构建了一种基于新生霉素衍生物的ROCS模型用于虚拟筛选。化合物13被鉴定为先导化合物，随后进行了系统的构效关系（SAR）研究。这些工作产生了化合物69，它对MCF7和SKBr3乳腺癌细胞系表现出强大的抗增殖活性。在4T1小鼠乳腺癌模型中，69表现出强大的肿瘤生长抑制和抗转移作用。化合物69作为一种靶向Hsp90 C端的强效抗肿瘤剂值得进一步的临床前研究。
