Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib

@article{Hantschel2008TargetSO,
  title={Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib},
  author={Oliver Hantschel and Uwe Rix and Giulio Superti-Furga},
  journal={Leukemia \& Lymphoma},
  year={2008},
  volume={49},
  pages={615 - 619}
}
Following the initial success of imatinib as frontline therapy for chronic myeloid leukemia (CML), several second-generation therapeutics have been developed with increased potency and the ability to inhibit the majority of imatinib-resistant mutations. Here, we review the current knowledge about the target specificity of the two new inhibitors nilotinib and dasatinib in comparison to imatinib, including the recent large-scale chemical proteomics screens. 
Mechanisms of resistance to BCR-ABL and other kinase inhibitors.
TLDR
The structural and mechanistic basis for imatinib resistance is focused on, and it is shown ways how next generations of BCR-ABL inhibitors and alternative targeting strategies have helped to offer effective treatment options forImatinib-resistant patients.
Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy
TLDR
Structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice
TLDR
Mechanisms of imatinib resistance and preclinical and clinical data with dasatinib and nilotinib which may have potential use for guiding second-line treatment decisions are discussed.
Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase.
TLDR
Overall, both dasatinib and nilotinib have shown superior efficacy compared with imatinib during the first year of treatment and longer-term follow-up is needed to confirm that this superiority is maintained over time.
Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia
TLDR
This review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.
Mechanisms of Resistance to Targeted Therapies in Chronic Myeloid Leukemia.
TLDR
The clinical efficacy of approved TKIs is summarized, the main mechanisms of TKI resistance are described, and different mechanisms of resistance have been identified, ranging from BCR-ABL1 kinase domain mutations to lack of adherence to therapy.
Off-Target Effects of BCR-ABL and JAK2 Inhibitors
TLDR
Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.
Development of an Effective Therapy for CML
TLDR
It is contended that the key to curing CML will involve strategies beyond targeting BCR-ABL, since primitive human CML stem cells are not dependent on BCRs, and a new generation of TKIs with activity against T315I is on the horizon.
BCR-ABL Point Mutations and TKI Treatment in CML Patients
TLDR
A third-generation BCR-ABL TKI, ponatinib was developed and had been already used in clinic and a lot of novel agents which can override BCR -ABL KD mutations including T315I are being developed.
Dasatinib and nilotinib in imatinib-resistant Philadelphia-positive chronic myelogenous leukemia: a ‘head-to-head comparison’
TLDR
A further consideration when deciding which agent to use, based on the efficacy and safety of dasatinib and nilotinib, involves the differences in both the imatinib-resistant and -intolerant patients enrolled in the pivotal studies for each agent, as well as other trial criteria.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 18 REFERENCES
Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.
TLDR
Two second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed and comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs were generated to predict potential side effects and novel medical uses.
The development of imatinib as a therapeutic agent for chronic myeloid leukemia.
TLDR
The preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia are reviewed.
Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor
TLDR
BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinIB-resistant BCR-ABL mutants and illustrates how molecular insight into kinase inhibitors resistance can guide the design of second-generation targeted therapies.
Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase.
TLDR
Dasatinib induced significant hematologic and cytogenetic responses in patients with imatinib resistance or intolerance, was well tolerated, and may represent a potent new therapeutic option for CML-AP.
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia.
TLDR
In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP.
The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib
TLDR
The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders.
Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl.
TLDR
AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models, suggests this is a promising new inhibitor for the therapy of CML and Ph+ ALL.
Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.
TLDR
The results highlight the strategy of screening existing clinical compounds against newly identified drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted therapy.
Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial.
TLDR
Dasatinib represents a safe and effective therapy for CP-CML resistant to conventional imatinib doses with improved cytogenetic and molecular response rates and progression-free survival relative to high-dose Imatinib.
Mechanisms of resistance to STI571 in Philadelphia chromosome-associated leukemias
TLDR
This review will highlight mechanisms of STI571 resistance in clinical samples as well as preclinical models, and suggest that BCR-ABL activity is restored in the majority of these cases of acquired resistance.
...
1
2
...