G-749 promotes receptor tyrosine kinase TYRO3 degradation and iInduces apoptosis in both colon cancer cell lines and xenograft mouse models

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Title
G-749 promotes receptor tyrosine kinase TYRO3 degradation and iInduces apoptosis in both colon cancer cell lines and xenograft mouse models
Author(s)
Hae Dong Kim; Eun Jung Park; Eun Kyoung Choi; Seuk Young Song; K L Hoe; Dong Uk Kim
Bibliographic Citation
Frontiers in Pharmacology, vol. 12, pp. 730241-730241
Publication Year
2021
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.
Keyword
G-749Anticancer drugTAM receptor tyrosine kinaseTyro3RIP processProtein degradation
ISSN
1663-9812
Publisher
Frontiers Media Sa
DOI
http://dx.doi.org/10.3389/fphar.2021.730241
Type
Article
Appears in Collections:
Division of Biomedical Research > Rare Disease Research Center > 1. Journal Articles
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