Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics.

ABSTRACT: Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by in vitro mutagenesis and microcalorimetry experiments

SUBMITTER: Lovera S 

PROVIDER: S-EPMC4659586 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature