The Structure of Dasatinib (BMS-354825) Bound to Activated ABL Kinase Domain Elucidates Its Inhibitory Activity against Imatinib-Resistant ABL Mutants

Abstract

Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL. Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL. Dasatinib (BMS-354825) is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL. It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL. The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants. (Cancer Res 2006; 66(11): 5790-7)

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…Dasatinib (Sprycel, Bristol-Myers Squibb) is an oral, second generation TKI that is 350 times more potent than imatinib in vitro [17][18][19]. In addition, it also is known to inhibit the Src family of kinases, which may also be important in blunting critical cell signaling pathways [20].…”

A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia; ceramide synthase and ceramide clearance genes

“…It acts as a competitive inhibitor at the ATP-binding site of BCR/ABL, preventing tyrosine phosphorylation of the substrate molecule and downstream signaling, causing growth arrest and apoptosis [11]. Dasatinib demonstrated significant activity against the mutations on its binding site including the ones causing poor prognosis in imatinib treatment.…”

Experimental treatment of human diffuse large B‐cell lymphoma xenografts by doxycycline alone or in combination with the anti‐CD20 chimeric monoclonal antibody rituximab

“…It is postulated that residues such as F359, which neighbor the activation loop, are critical for maintaining the particular inactive imatinib-bound conformation. The F359 residue is also involved in van der Waals contacts with both imatinib and the activation loop in the imatinib-bound form [12]. F359 mutations that are associated with amino acid substitutions in the catalytic region include (Phe359Ala) F359A, Phe359Val (F359V), Phe359Ile (F359I), or Phe359Cys (F359C) as detected in this patient.…”

“…Dasatinib was originally developed as a Src kinase inhibitor and is structurally distinct from imatinib. Compared with imatinib, dasatinib exhibits increased potency but reduced selectivity and binds both active and inactive conformations of Abl [12]. Overriding imatinib resistance with dasatinib in other mutations involving F359 residue, such as F359I, has been reported and its efficacy against BCR-ABL with mutations at this site is explained by the fact that it does not reside near this residue [12,14].…”