FLT3 (wild-type and mutant, including ITD/TKD), SYK

Class

Small molecule multikinase inhibitor

Pathway

Reversible type I FLT3 inhibition plus SYK/JAK1/2/RSK1/2/TAK1-TAB1/mutant KIT inhibition, modulating downstream p-STAT5 and p-ERK signaling

FLT3 is a receptor found on the surface of early blood-forming cells. It normally receives a growth signal and helps these cells mature and divide in a controlled way. In a substantial subset of acute myeloid leukemia (AML), the gene encoding FLT3 is altered—most often by an internal tandem duplication (ITD) or a point mutation in the tyrosine kinase domain (TKD)—so that the receptor stays switched on even without its natural signal. This constant activity drives two intracellular relay systems, STAT5 and ERK, that push leukemic cells to survive and multiply. Blocking mutant FLT3 is therefore a rational strategy to slow disease growth. Because leukemic cells can develop alternative ways to keep these same relay systems active even when FLT3 itself is blocked, some inhibitors are designed to also hit related kinases, including SYK, which participates in parallel survival signaling within the bone marrow environment. A multikinase inhibitor spanning FLT3 (wild-type and mutant forms) together with SYK and other kinases aims to suppress both the primary driver and the escape routes leukemic cells might otherwise use, broadening and prolonging the anti-leukemic effect compared with a narrowly selective FLT3 agent.