Deciphering the Anti-Leukemic Potential of KW-2449: A Multi-Target Kinase Inhibitor in AML Therapy

The activation of FLT3 kinase, which is linked to adverse outcomes in AML and affects 30-40% of patients, is targeted by KW-2449, a compound that inhibits multiple kinases including FLT3, FGFR1, Abl, and Abl-T315 with varying IC50 values. It also has a modest effect on c-Src, JAK2, and c-Kit kinases but minimally affects PDGFR, Fms, IGF1R, and EGFR at a concentration of 1.0 μmol/L. Notably, it uniquely targets Aurora A kinase. The study explores KW-2449's potential in combating leukemia in cell lines with constitutively active FLT3 and in those with wild-type FLT3. In FLT3-ITD positive MOLM-13 cells, KW-2449 reduces phosphorylated FLT3 and STAT5, leading to G1 arrest and apoptosis. It also shows strong inhibitory activity against 32D cells with various FLT3 mutations and inhibits the growth of wild-type RS4;11 cells, reducing phosphorylated Histone H3 and inducing G2/M arrest and apoptosis.

In vivo studies in SCID mice with MOLM-13 leukemia demonstrate dose-dependent tumor growth inhibition with KW-2449, with complete remission at a dose of 20 mg/kg without significant weight loss. PK/PD studies show a reduction in phosphorylated FLT3 and STAT5 levels in tumors post-treatment. Furthermore, oral administration of 20 mg/kg KW-2449 extends survival in xenograft models with MOLM-13 or 32D/FLT3-D835Y cells. KW-2449 also exhibits concentration-dependent growth inhibition in primary AML samples with FLT3 mutations, correlating with reduced P-FLT3 and P-STAT5 levels.

Given its potent and unique kinase inhibition profile, KW-2449 is anticipated to be effective in treating AML with FLT3 mutations, FLT3 wild-type AML, imatinib-resistant CML, ALL, and other hematological malignancies. It is currently under investigation in a Phase I clinical trial for patients with relapsed or refractory AML, MDS, CML, and ALL.