Discovery of Highly Potent and Selective Pan-Aurora Kinase Inhibitors with Enhanced in Vivo Antitumor Therapeutic Index
详细信息 查看全文
- 作者：Gang Liu ; Sunny Abraham ; Lan Tran ; Troy D. Vickers ; Shimin Xu ; Michael J. Hadd ; Sheena Quiambao ; Mark W. Holladay ; Helen Hua ; Julia M. Ford Pulido ; Ruwanthi N. Gunawardane ; Mindy I. Davis ; Shawn R. Eichelberger ; Julius L. Apuy ; Dana Gitnick ; Michael F. Gardner ; Joyce James ; Mike A. Breider ; Barbara Belli ; Robert C. Armstrong ; Daniel K. Treiber
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：55
- 期：7
- 页码：3250-3260
- 全文大小：451K
- 年卷期：v.55,no.7(April 12, 2012)
- ISSN：1520-4804
文摘
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.