Abstract: Aberrant tyrosine-protein kinase Mer (MerTK) expression triggers prosurvival signaling
and contributes to cell survival, invasive motility, and chemoresistance in many kinds of cancers.
In addition, recent reports suggested that MerTK could be a primary target for abnormal platelet
aggregation. Consequently, MerTK inhibitors may promote cancer cell death, sensitize cells to
chemotherapy, and act as new antiplatelet agents. We screened an inhouse chemical library to
discover novel small-molecule MerTK inhibitors, and identified AZD7762, which is known as
a checkpoint-kinase (Chk) inhibitor. The inhibition of MerTK by AZD7762 was validated using an
in vitro homogeneous time-resolved fluorescence (HTRF) assay and through monitoring the decrease
in phosphorylated MerTK in two lung cancer cell lines. We also determined the crystal structure
of the MerTK:AZD7762 complex and revealed the binding mode of AZD7762 to MerTK. Structural
information from the MerTK:AZD7762 complex and its comparison with other MerTK:inhibitor
structures gave us new insights for optimizing the development of inhibitors targeting MerTK.
Keywords: MerTK; AZD7762; TAM family kinase; X-ray crystallography
