Receptor-type tyrosine-protein kinase FLT3 (FLT3) (FLT3)

Receptor-type tyrosine-protein kinase FLT3 (FLT3) is a class III receptor tyrosine kinase that plays a fundamental role in the proliferation, survival, and differentiation of hematopoietic progenitor cells [2, 16, 18]. Under normal physiological conditions, FLT3 is activated by its ligand (FLT3LG), triggering signaling cascades such as the PI3K/AKT/mTOR, RAS/RAF/MAPK, and JAK/STAT pathways [1, 6, 19]. However, FLT3 is one of the most frequently mutated genes in acute myeloid leukemia (AML), with internal tandem duplications (FLT3-ITD) and tyrosine kinase domain (FLT3-TKD) mutations leading to constitutive, ligand-independent activation [13, 16, 18]. These mutations are associated with high blast counts, increased relapse rates, and overall poor prognosis in leukemia patients [6, 14, 16]. Consequently, FLT3 has become a primary therapeutic target, leading to the development of several small-molecule tyrosine kinase inhibitors (TKIs) [3, 10, 13]. These inhibitors are categorized into Type I (targeting both ITD and TKD mutations) and Type II (primarily targeting ITD mutations), and are used either as monotherapy or in combination with standard chemotherapy to improve clinical outcomes [10, 13, 17]. Notable safety concerns associated with these therapies include QTc prolongation, myelosuppression, and the development of secondary resistance mutations [3, 8, 10].

Other names

FL cytokine receptorFetal liver kinase-2FLK-2Fms-like tyrosine kinase 3FLT-3Stem cell tyrosine kinase 1STK-1CD135

Competitive inhibition of the ATP-binding site within the tyrosine kinase domain, blocking autophosphorylation and downstream signaling pathways such as PI3K/AKT and MAPK (Type I and Type II inhibition) [3, 10, 13].