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.
Highlights
Tyrosine-protein kinase Mer (MerTK) belongs to the family of Tyro3/Axl/Mer (TAM) receptor kinases, which are homeostatic regulators of reproduction, immune function, blood vessels, hematopoiesis, and the nervous system, mainly through the phagocytosis of apoptotic cells [1]
As knockdown of MerTK by small-hairpin RNA caused apoptosis in A549 cells [14], we investigated whether AZD7762 treatment induced apoptosis in lung cancer cells
We verified the inhibitory activity of AZD7762 for MerTK using in vitro kinase and cell-based assays
Summary
Tyrosine-protein kinase Mer (MerTK) belongs to the family of Tyro3/Axl/Mer (TAM) receptor kinases, which are homeostatic regulators of reproduction, immune function, blood vessels, hematopoiesis, and the nervous system, mainly through the phagocytosis of apoptotic cells [1]. TAM family proteins share the common biological ligand growth-arrest-specific 6 (Gas6) for their functional activation [3], MerTK can recognize other ligands, such as protein S and galectin-3, through its extracellular immunoglobulin and fibronectin-like domains [2,4,5] The binding of these ligands to MerTK induces the autophosphorylation of tyrosine residues in the activation loop of the MerTK kinase domain (Tyr749, Tyr753, and Tyr754) [6], resulting in the recruitment of adaptor proteins including Grb, LimD4, and Vav1 [7,8,9,10], and the activation of downstream enzymes such as PI3Ks, MAPKs, and GTPases [2,7]. Similar results were shown in non-small cell lung cancer (NSCLC) cells [14]
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