Deciphering the molecular mechanism of FLT3 resistance mutations

• Published in: The FEBS journal Vol. 287; no. 15; pp. 3200 - 3220
• Main Authors: Georgoulia, Panagiota S., Bjelic, Sinisa, Friedman, Ran
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.08.2020
• Subjects: Acute myeloid leukemia; Aminopyridines - pharmacology; Benzothiazoles - pharmacology; Biochemistry; Biokemi; Catalytic activity; Clinical trials; Computer simulation; computers; Drug development; Drug resistance; Drug Resistance, Neoplasm - genetics; drugs; Enzyme kinetics; FLT3; fms-Like Tyrosine Kinase 3 - chemistry; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Humans; Inhibitors; kinase inhibitors; Kinases; Kinetics; leukaemia; Leukemia; Mathematical models; Molecular Biology; molecular dynamics; Molekylärbiologi; Mutation; myeloid leukemia; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Perturbation; Phenylurea Compounds - pharmacology; Protein Conformation; Protein Kinase Inhibitors - pharmacology; Protein structure; Protein-tyrosine kinase; Proteins; Pyrroles - pharmacology; Reaction kinetics; Resistant mutant; Tyrosine; leukaemia; kinase inhibitors; molecular dynamics; FLT3; enzyme kinetics

FMS‐like tyrosine kinase 3 (FLT3) has been found to be mutated in ~ 30% of acute myeloid leukaemia patients. Small‐molecule inhibitors targeting FLT3 that are currently approved or still undergoing clinical trials are subject to drug resistance due to FLT3 mutations. How these mutations lead to drug...