Over 30% of patients with newly diagnosed
AML have
FLT3 mutations, which are implicated in a significant portion of AML cases. FLT3 inhibitors are recommended treatments; however, resistance to these inhibitors is a major challenge.
AXL-mediated activation of FLT3 and TKD mutations contribute to this resistance. Therefore, a dual FLT3/AXL inhibitor with strong FLT3-TKD inhibition could offer improved efficacy as a novel AML treatment.
JRF104 is a potent FLT3/AXL dual inhibitor with low nanomolar IC50 values for both targets. It has shown to effectively inhibit the proliferation of cells with FLT3-ITD mutations and has a broad antiproliferation activity against all FLT3 mutation types, including the resistant F691L mutation. JRF104 also reduces cell migration by blocking AXL-regulated pathways and has demonstrated significant
tumor growth inhibition in multiple xenograft models at various doses. Notably, it has shown complete tumor regression in some cases.
In combination with an anti-
PD-1 antibody, JRF104 has enhanced anti-tumor effects in a syngeneic model, suppressing key signaling pathways. The compound has shown high oral bioavailability across species and has been well-tolerated in preclinical toxicology studies, with defined human no observed adverse effect level (HNSTD) and no observed effect level (NOEAL) doses established.
In conclusion, JRF104 has exhibited potent inhibition of FLT3 and strong antitumor efficacy in preclinical studies, suggesting its potential to overcome resistance mechanisms associated with AXL and FLT3-TKD mutations. These findings indicate that JRF104 is a promising candidate for clinical development as a treatment for AML patients with FLT3 mutations.
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.
