期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 7, 期 12, 页码 1044-1049出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00221
关键词
MerTK inhibitors; MerTK; macrocycle; pyrrolopyrimidine; TAM kinase; structure-based drug design
资金
- University Cancer Research Fund
- National Cancer Institute, National Institute of Health [HHSN261200800001E]
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 EC50 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.
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