Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571.

摘要: STI571, a selective inhibitor of Bcr-Abl, has been successful therapeutic agent in clinical trials for chronic myelogenous leukemia. Chronic phase leukemia patients treated with STI571 have durable responses; however, most responding blast relapse despite continued therapy. Co-crystallization studies Abl kinase and an STI571-related compound identify specific amino acid residues as critical to binding, one which, T315, characterized acquired Thr Ile mutation relapsed patients. Other studies, suggest that mutations other than these predicted contact points are capable conferring resistance Using variety models binding the kinase, we performed extensive mutational analysis sites might alter sensitivity STI571. Although many between result kinase-inactive protein, additional render less sensitive demonstrate broad range possibilities now becoming evident.