Design and Synthesis of Novel Human Epidermal Growth Factor Receptor 2 (HER2)/Epidermal Growth Factor Receptor (EGFR) Dual Inhibitors Bearing a Pyrrolo[3,2-d]pyrimidine Scaffold

被引:193
作者
Ishikawa, Tomoyasu [1 ]
Seto, Masaki [1 ]
Banno, Hiroshi [1 ]
Kawakita, Youichi [1 ]
Oorui, Mami [1 ]
Taniguchi, Takahiko [1 ]
Ohta, Yoshikazu [1 ]
Tamura, Toshiya [1 ]
Nakayama, Akiko [1 ]
Miki, Hiroshi [1 ]
Kamiguchi, Hidenori [1 ]
Tanaka, Toshimasa [1 ]
Habuka, Noriyuki [1 ]
Sogabe, Satoshi [1 ]
Yano, Jason [2 ]
Aertgeerts, Kathleen [2 ]
Kamiyama, Keiji [1 ]
机构
[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Fujisawa, Kanagawa 2518555, Japan
[2] Takeda San Diego Inc, Struct Biol, San Diego, CA 92121 USA
关键词
TYROSINE KINASE INHIBITOR; HUMAN-BREAST-CANCER; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; TRASTUZUMAB; DISCOVERY; CETUXIMAB; SURVIVAL; ZD1839; DOMAIN;
D O I
10.1021/jm2008634
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors' ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HERO inhibitory activities as well as tumor growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, '34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
引用
收藏
页码:8030 / 8050
页数:21
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