XL092 is a Potent Axl, Mer and C-Met kinase Inhibitor
Posted On 2022-01-08
Human Axl belongs to the TAM subfamily of receptor tyrosine kinases that includes Mer.
TAM kinases contain two immunoglobulin-like domains and two fibronectin type III domains. Many cancer cells exhibit overexpressed Axl. And it is initially cloned from patients with chronic myelogenous leukemia.
Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, and breast cancer, et al.
Cabozantinib, an inhibitor of MET, VEGFR2, AXL, and MER. And it shows significant clinical activity in multiple solid tumors.
In this article, we will introduce another potent MET inhibitor, XL092. Besides, XL092 has a similar target profile to cabozantinib but with a significantly shorter clinical half-life and pharmacokinetic properties.
XL092 is an ATP-competitive inhibitor of multiple RTKs including MET, VEGFR2, AXL, and MER.
The IC50 values are of 15 nM, 1.6 nM, 3.4 nM, and 7.2 nM in cell-based assays, respectively. In vitro, treatment of human macrophages with XL092 inhibits macrophage efferocytosis with IC50 of 81 nM.
Besides, XL092 promotes repolarization from an M2 anti-inflammatory to an M1 pro-inflammatory phenotype.
In vivo, XL092 has a T1/2 of 5.4 hours, a CL of 43 mL/hr•kg after tail vein injection. Additionally, XL092 exhibits a T1/2 of 7.1 hours and a Cmax of 11.4 μM for rats.
XL092 inhibits tumor angiogenesis in a dose-dependent manner. What’s more, treatment with XL092 alone increases circulating levels of CD4+ and CD8+ T cells and B cells, Additionally, the combination of XL092 and anti–PD-1 exhibits greater anti-tumor activity than either agent alone.
Anti–PD-1 and XL092 combination decreases levels of proliferating and IFNg-producing effector T cells in circulation.
In conclusion, XL092 is an oral tyrosine kinase inhibitor to target VEGF receptors, MET, and other kinases. It is a promising agent for tumor research.
. Jeff Hsu, et al. 10.1158/1535-7163.TARG-21-P248