Fms-like tyrosine kinase 3 (FLT3), Vascular endothelial growth factor receptor (VEGFR), and Rearranged during transfection (RET) (FLT3, VEGFR, RET)

This target profile represents a group of three distinct Receptor Tyrosine Kinases (RTKs): Fms-like tyrosine kinase 3 (FLT3), Vascular endothelial growth factor receptor (VEGFR), and Rearranged during transfection (RET). FLT3 is a class III RTK primarily expressed in hematopoietic progenitor cells, where it regulates the proliferation and differentiation of stem cells (UniProt P36888). The VEGFR family, including VEGFR1, VEGFR2, and VEGFR3, are master regulators of angiogenesis and lymphangiogenesis, facilitating the blood supply required for tumor growth (UniProt P35968). RET is a proto-oncogene essential for the development of the enteric nervous system and the kidneys, but its oncogenic activation via fusions or mutations drives several malignancies (UniProt P07949). These proteins are frequently co-targeted by multi-kinase inhibitors (MKIs) to achieve a synergistic anti-tumor effect by inhibiting cell survival, angiogenesis, and the tumor microenvironment simultaneously. Clinically, FLT3 mutations are hallmark drivers in acute myeloid leukemia, while RET alterations are prevalent in medullary thyroid and lung cancers. VEGFR inhibition is a standard approach in treating highly vascularized tumors like renal cell carcinoma. Therapeutic challenges include managing off-target toxicities such as hypertension and QTc prolongation, which often arise from the broad inhibitory profile of these drugs.

Other names

CD135FLK2STK1FLT1 (VEGFR1)FLK1 (VEGFR2)KDR (VEGFR2)FLT4 (VEGFR3)CDHF12HSCR1PTCMEN2AMEN2B

These targets are inhibited by small-molecule tyrosine kinase inhibitors that bind to the intracellular ATP-binding pocket of the kinase domain. This binding prevents the autophosphorylation of the receptor and the subsequent activation of downstream signaling cascades, including the PI3K/AKT/mTOR, RAS/RAF/MEK/ERK, and JAK/STAT pathways, which are critical for cell survival, growth, and motility (PubMed: 30225323, 28438666).