生物活性

• 靶点	Axl IC50:27nM

• 描述Axl belongs to the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (RTK). The extracellular portion of AXL has properties and structural elements similar to cell adhesion molecules that may participate in cell-to-cell contacts that are not fully understood. In addition to this, AXL binds to the soluble ligand of GAS6 (growth arrest-specific 6) that activates downstream signaling networks responsible for its biological effects. GAS6 binding to AXL results in receptor dimerization and AXL autophosphorylation. This activation results in downstream signaling to the PI3K/AKT, MAPK, and NF-κB pathways. TP-0903 is an Axl kinase inhibitor with IC₅₀ of 27 nM. TP-0903 was active in cell viability assays with an IC₅₀ of 6 nM against the pancreatic cancer cell line PSN-1. PSN-1 cells were stimulated with GAS6 in the presence of the concentrations of 0.03, 0.1, 0.3, 1, 3 or 10 μM of TP-0903. TP-0903 concentration-dependently suppressed phospho-AKT and phospho-AXL levels with EC₅₀s of 305 and 222 nM, respectively^[3]. Tumor cells derived from chronic lymphocytic leukemia (CLL) patients were treated by 0.1 μM of TP-0903 and the results were that TP-0903 induced PARP cleavage and caspase-3 activation in 3 of 4 patient samples. In another assay, purified CLL B cells sensitive to TP-0903 were cultured alone or cocultured with CLL BMSCs from 3 different CLL patients followed by treatment with 0.1 mM or 0.175 mM of TP-0903 for 24 h. It was suggested that TP-0903 overcomes CLL BMSC-mediated protection of CLL B cells from apoptosis^[4].
• 作用机制TP-0903 is an Axl kinase inhibitor. Structural study suggested that TP-0903 interacted with the ATP binding site of Axl kinase. In detail, the pyrimidine nitrogen of TP-0903 was involved in a hydrogen-binding interaction with the Met623 residue in the hinge region of the kinase^[3].