Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors

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• 作者：Xiaodong Wang ; Jing Liu ; Weihe Zhang ; Michael A. Stashko ; James Nichols ; Michael J. Miley ; Jacqueline Norris-Drouin ; Zhilong Chen ; Mischa Machius ; Deborah DeRyckere ; Edgar Wood ; Douglas K. Graham ; H. Shelton Earp ; Dmitri Kireev ; Stephen V. Frye
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1044-1049
• 全文大小：496K
• ISSN：1948-5875

文摘

Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC<sub>50sub> below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.