Mer kinase is a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases. Mer is ectopically expressed in acute lymphoblastic leukemia (ALL), and other cancers such as lymphoblastic and myeloid leukemia, glioblastoma, non-small cell lung cancer, melanoma, and pediatric rhabdo-myosarcoma. When Mer is inhibited through si/sh-RNA knockdown, cells are more susceptible to death after chemotherapy treatment, and the onset of disease in a xenograft mouse model of leukemia is significantly delayed. Therefore Mer provides a novel therapeutic target for the treatment of ALL and other Mer-related diseases either by the small molecule inhibitors or the combination with chemotherapeutic agents.  Based on the X-ray co-crystal structure on Mer protein of our previous bicyclic pyrazolo[3,4-d]pyrimidine scaffold, we used pseudo ring design strategy and designed a novel monocyclic pyrimidine scaffold. The recently resolved X-ray co-crystal structures on Mer protein of this monocyclic pyrimidine scaffold have confirmed our structure-based design strategy. The Structure-Activity Relationships (SAR) on this novel scaffold has been well studied; lead compounds with nanomolar to subnanomolar IC50 activity against Mer kinase in both enzymatic and cell-based assays were also identified.

Structure-based design and synthesis of novel 2,4-diaminopyrimidine analogs as Mer kinase inhibitors in the treatment of cancer

246th National Meeting (2013)

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