Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL |
| |
Authors: | Azam Mohammad Latek Robert R Daley George Q |
| |
Institution: | Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA. |
| |
Abstract: | The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds. This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|