Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors

详细信息    查看全文

• 作者：Liping H. Pettus ; Kristin L. Andrews ; Shon K. Booker ; Jie Chen ; Victor J. Cee ; Frank Chavez Jr. ; Yuping Chen ; Heather Eastwood ; Nadia Guerrero ; Bradley Herberich ; Dean Hickman ; Brian A. Lanman ; Jimmy Laszlo III ; Matthew R. Lee ; J. Russell Lipford ; Bethany Mattson ; Christopher Mohr ; Yen Nguyen ; Mark H. Norman ; David Powers ; Anthony B. Reed ; Karen Rex ; Christine Sastri ; Nuria Tamayo ; Paul Wang ; Jeffrey T. Winston ; Bin Wu ; Tian Wu ; Ryan P. Wurz ; Yang Xu ; Yihong Zhou ; Andrew S. Tasker ; Hui-Ling Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6407-6430
• 全文大小：1017K
• 年卷期：0
• ISSN：1520-4804

文摘

The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low K_m for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.