Acute Myeloid Leukemia (AML) is often linked with the
FLT3 Internal tandem duplication mutation (FLT3-ITD), which is found in about a third of cases. This mutation leads to increased cell proliferation and inhibition of apoptosis.
Quizartinib, a second-generation FLT3 inhibitor, has shown efficacy in treating
AML but has a limited response duration due to secondary mutations like D835X, which render FLT3 constitutively active. Type 2 inhibitors, such as Quizartinib, are ineffective against this mutated form of FLT3.
A novel therapeutic agent,
ON150030, has been developed to overcome this challenge. Structural studies indicate that ON150030 binds to the active form of FLT3, making it a Type 1 inhibitor. This allows ON150030 to inhibit both wildtype and mutant forms of FLT3, including those with the D835Y mutation, which Quizartinib cannot. ON150030 has demonstrated potent inhibitory effects on FLT3 in vitro and is characterized as an irreversible inhibitor.
Biological studies have shown that ON150030 specifically inhibits the growth of MV4-11 cells with the FLT3-ITD mutation and reduces the activity of
MAPK and
PI3K/
AKT pathways. Additionally, it counteracts the
JAK-independent phosphorylation of
STAT5 associated with FLT3-ITD.
Future plans include examining the effects of FLT3 and its mutant isoforms on mouse myeloid cells and comparing the impacts of ON150030 and Quizartinib on these cells. Given that ON150030 also inhibits
SRC, a known inducer of resistance to targeted therapies in
leukemias, researchers will test the drug's sensitivity in cells with introduced SRC.
Cytotoxicity and biochemical assays are planned for patient-derived primary AML cells treated with ON150030. Mouse xenograft models will help determine the potential synergy of ON150030 with standard chemotherapy agents and its ability to inhibit
cancer progression in vivo.
The ultimate goal of the project is to establish ON150030 as a viable component of combination therapies for all AML patients with FLT3 mutations, potentially leading to sustained remission.
The research was presented by Helya Ghaffari, M.V. Ramana Reddy, and colleagues at the American Association for Cancer Research Annual Meeting in 2017.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
