New resistance mechanisms for small molecule kinase inhibitors of Abl kinase

Abstract

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with Imatinib in patients with chronic myelogenous leukaemia (CML). Second generation Bcr-Abl inhibitors, such as Nilotinib and Dasatinib, are able to overcome most Imatinib- resistant mutants, with the exception of the T315I substitution. Structural studies of Abl wild-type and T315I mutant have provided better understanding of how this mutation leads to resistance and have been used to support the drug design process for the development of inhibitors able to target the T315I substitution.