Author:

Keywords:

Animals, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Synergism, Humans, K562 Cells, Leukemia, Myeloid, Acute, Mice, Mutant Proteins, Mutation, Missense, Protein Kinase Inhibitors, Protein Structure, Tertiary, Pyridones, Pyrimidines, Xenograft Model Antitumor Assays, fms-Like Tyrosine Kinase 3, Science & Technology, Life Sciences & Biomedicine, Hematology, RECEPTOR TYROSINE KINASES, ALPHA-1-ACID GLYCOPROTEIN, TANDEM DUPLICATIONS, ACTIVATING MUTATION, CELLS, APOPTOSIS, SURVIVAL, MER, TRANSDUCTION, SORAFENIB, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Immunology, 3101 Biochemistry and cell biology, 3201 Cardiovascular medicine and haematology, 3213 Paediatrics

Abstract:

Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML). G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.