Abstract
G-749 is an FLT3 kinase inhibitor that was originally developed as a treatment for acute myeloid leukemia. Some FLT3 kinase inhibitors are dual kinase inhibitors that inhibit the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase family and are used to treat solid cancers such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). AXL promotes metastasis, suppression of immune response, and drug resistance in NSCLC and TNBC. G-749, a potential TAM receptor tyrosine kinase inhibitor, and its derivative SKI-G-801, effectively inhibits the phosphorylation of AXL at nanomolar concentration (IC50 = 20 nM). This study aimed to investigate the anticancer effects of G-749 targeting the TAM receptor tyrosine kinase in colon cancer. Here, we demonstrate the potential of G-749 to effectively inhibit tumorigenesis by degrading TYRO3 via regulated intramembrane proteolysis both in vitro and in vivo. In addition, we demonstrated that G-749 inhibits the signaling pathway associated with cell proliferation in colon cancer cell lines HCT15 and SW620, as well as tumor xenograft mouse models. We propose G-749 as a new therapeutic agent for the treatment of colon cancer caused by abnormal TYRO3 expression or activity.
Highlights
G-749 is an FLT3 kinase (FMS-like tyrosine kinase 3, FLT3) inhibitor, which was originally developed as a treatment for acute myeloid leukemia (AML) and later designated as an orphan drug by the Federal Drug Administration (FDA) in 2018
Results showed that G-749 was less toxic to CCD-18co normal colon fibroblast cells compared to colon cancer cells (Supplementary Figures S2A,B)
MER and TYRO3 were expressed in all the colon cancer cell lines
Summary
G-749 is an FLT3 kinase (FMS-like tyrosine kinase 3, FLT3) inhibitor, which was originally developed as a treatment for acute myeloid leukemia (AML) and later designated as an orphan drug by the Federal Drug Administration (FDA) in 2018. Some FLT3 kinase inhibitors such as MRX-2843, UNC 2025, Giltertinib, and ONO-7475 are dual kinase inhibitors that inhibit TAM (TYRO, AXL, MER) receptor tyrosine kinase (RTK) in non-small cell lung cancer (NSCLC) and breast cancer (Zhang et al, 2014; Minson et al, 2016; Mori et al, 2017; Wu et al, 2018b; Okura et al, 2020). Giltertinib and ONO-7475 are AXL/FLT3 dual kinase inhibitors that have been reported to inhibit adaptive resistance to early EGFR-TKI treatment in EGFR-mutant NSCLC (Mori et al, 2017; Okura et al, 2020). Many FLT3 kinase inhibitors act as dual kinase inhibitors that inhibit TAM RTK, the potential of G-749 as a TAM RTK inhibitor remains unclear
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