Fms-like tyrosine kinase 3 (FLT3-D835V) (FLT3-D835V)

Fms-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase that plays a pivotal role in the proliferation and survival of hematopoietic progenitor cells (UniProt: P36888). The D835V mutation is a point mutation located in the activation loop of the second tyrosine kinase domain (TKD), which results in the constitutive activation of the kinase regardless of ligand binding (PubMed: 22653454). This specific mutation is observed in roughly 7-10% of acute myeloid leukemia (AML) cases and is a common mechanism of acquired resistance to type II FLT3 inhibitors like quizartinib, which only bind the inactive conformation of the kinase (NIH: PMC4233494). Unlike type II inhibitors, type I inhibitors such as gilteritinib and midostaurin are capable of binding to the active conformation of the kinase, making them effective against the D835V variant (FDA: Gilteritinib Prescribing Information). Consequently, FLT3-D835V serves as both a therapeutic target and a critical biomarker for determining treatment strategies in relapsed or refractory AML.

Other names

FLT3-TKDCD135Fetal liver kinase 2FLK-2Stem cell tyrosine kinase 1STK-1

Type I tyrosine kinase inhibition, where the drug binds to the ATP-binding pocket of the kinase in its active conformation, preventing autophosphorylation and downstream signaling (PubMed: 29074728).