Discovery and Optimization of Macrocyclic Quinoxaline-pyrrolo-dihydropiperidinones as Potent Pim-1/2 Kinase Inhibitors

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• 作者：Victor J. Cee ; Frank Chavez Jr. ; Bradley Herberich ; Brian A. Lanman ; Liping H. Pettus ; Anthony B. Reed ; Bin Wu ; Ryan P. Wurz ; Kristin L. Andrews ; Jie Chen ; Dean Hickman ; Jimmy Laszlo III ; Matthew R. Lee ; Nadia Guerrero ; Bethany K. Mattson ; Yen Nguyen ; Christopher Mohr ; Karen Rex ; Christine E. Sastri ; Paul Wang ; Qiong Wu ; Tian Wu ; Yang Xu ; Yihong Zhou ; Jeffrey T. Winston ; J. Russell Lipford ; Andrew S. Tasker ; Hui-Ling Wang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：408-412
• 全文大小：344K
• 年卷期：0
• ISSN：1948-5875

文摘

The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure–activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC₅₀ = 25 nM) and in vivo (pBAD EC₅₀ = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.