Preclinical Characterization of XL092, a Novel Receptor Tyrosine Kinase Inhibitor of MET, VEGFR2, AXL, and MER

by Selleckchem | Jan 15 2024

The multi-receptor tyrosine kinase inhibitor XL092 has been developed to inhibit the activity of oncogenic targets, including MET, VEGFR2, and the TAM family of kinases TYRO3, AXL and MER. Presented here is a preclinical evaluation of XL092. XL092 causes a significant decrease in tumor MET and AXL phosphorylation (P < 0.01) in murine Hs 746T xenograft models relative to vehicle, and a 96% inhibition of VEGFR2 phosphorylation in murine lungs. Dose-dependent tumor growth inhibition with XL092 was observed in various murine xenograft models, with dose-dependent tumor regression seen in the NCI-H441 model. Tumor growth inhibition was enhanced with the combination of XL092 with anti-PD-1, anti-programmed death ligand-1 (PD-L1), or anti-CTLA-4 compared with any of these agents alone in the MC38 murine syngeneic model and with anti-PD-1 in the CT26 colorectal cancer survival model. In vivo, XL092 promoted a decrease in the tumor microvasculature and significant increases of peripheral CD4+ T cells and B cells and decreases in myeloid cells versus vehicle. Significant increases in CD8+ T cells were also observed with XL092 plus anti-PD-1 or anti-PD-L1 versus vehicle. In addition, XL092 promoted M2 to M1 repolarization of macrophages in vitro and inhibited primary human macrophage efferocytosis in a dose-dependent manner. In summary, XL092 was shown to have significant antitumor and immunomodulatory activity in animal models both alone and in combination with immune checkpoint inhibitors, supporting its evaluation in clinical trials.

Comments:

The description of XL092's preclinical evaluation is quite comprehensive! It seems to demonstrate promising characteristics in inhibiting various oncogenic targets like MET, VEGFR2, and TAM family kinases (TYRO3, AXL, MER). This multi-receptor tyrosine kinase inhibitor shows efficacy in reducing tumor phosphorylation in murine models, resulting in tumor growth inhibition and, notably, regression in certain models like NCI-H441.

Moreover, its synergistic effects with immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, and anti-CTLA-4) in murine models, especially the enhanced tumor growth inhibition in combination therapies, are intriguing. The observed changes in the tumor microenvironment, such as decreased microvasculature, alterations in immune cell populations (increases in CD4+ and CD8+ T cells and B cells, decreases in myeloid cells), and the shift from M2 to M1 macrophage polarization, indicate its potential immunomodulatory effects.

Additionally, XL092's inhibition of primary human macrophage efferocytosis further illustrates its impact on immune responses. Altogether, these findings strongly suggest that XL092 exhibits both antitumor activity and significant effects on the immune system, warranting further exploration in clinical trials.

It's quite exciting to see compounds like XL092 demonstrating such multifaceted potential in both directly targeting tumors and modulating the immune system to enhance the anti-cancer response. Clinical trials will be crucial to validate these preclinical findings and assess its safety and efficacy in human subjects.