Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer

被引:251
作者
Cai, Xiong [1 ]
Zhai, Hai-Xiao [1 ]
Wang, Jing [1 ]
Forrester, Jeffrey [1 ]
Qu, Hui [1 ]
Yin, Ling [1 ]
Lai, Cheng-Jung [1 ]
Bao, Rudi [1 ]
Qian, Changgeng [1 ]
机构
[1] Curis Inc, Cambridge, MA 02138 USA
关键词
HISTONE DEACETYLASE INHIBITORS; ERBB RECEPTORS; RESISTANCE; CELLS; COMBINATION; MECHANISMS; ONCOGENE; MUTATION; THERAPY; DESIGN;
D O I
10.1021/jm901453q
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
By incorporating historic deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series OF compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug Candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, respectively. In most tumor Cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results Suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
引用
收藏
页码:2000 / 2009
页数:10
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