Discovery of a new binding pocket of FKBP52-N and design of two novel neurotrophic ligands of FKBP12
Year: 2002
Type: conference-abstract
Abstract: In chronic myelogenous leukemia (CML), a reciprocal balanced chromosomal translocation in haematopoietic stem cells produces the BCR-ABL hybrid gene, which encodes a constitutively activated kinase.STI571, marketed as imatinib, is a potent ATP-competitive inhibitor of c-Abl (IC50 188 nM).Despite the efficacy of the drug in stable-phase CML, in advanced leukemias, where there is a high frequency of DNA mutation, many patients relapse with point mutations in the kinase domain.We have determined the crystal structure of STI571 in complex with human Abl kinase (spacegroup C2221) and determined the inhibitry activity of STI571 towards many of the Abl kinase mutants.The structure shows that STI571 stabilises an inactive conformation of the protein, thus comfirming Schindlers findings (Science 2000(Science , 289:1938(Science -1942) ) for murine Abl-kinase in complex with a structurally-related inhibitor (spacegroup F222).These studies allow us to rationalise the decreased sensitivity of mutant Bcr-Abl to STI571.Point mutations such as T315I in the ATP-binding site result in loss of a hydrogen bond and steric hindrance to the binding of STI571 (IC50T315I (STI571) > 10 µM).Mutations in the glycine-rich loop such as E255V (IC50 (STI571) 3.5 µM), E255K and Y253H (IC50 (STI571) >10 µM), destabilise the unusual conformation that this loop adopts in the inactive state, as does H396P in the activation loop.The variety and spread of these and other mutants makes it a challenge to design drugs to overcome resistance.
Institution: Novartis (Switzerland)
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W2015799325