JRF104: A Novel FLT3/AXL Dual Inhibitor with Significant FLT3-TKD Inhibitory Activity

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.