Bcr-Abl tyrosine kinase inhibitors: a patent review

Desogus, Andrea; Schenone, Silvia; Brullo, Chiara; Tintori, Cristina; Musumeci, Francesca

doi:10.1517/13543776.2015.1012155

Cited by 17 publications

(12 citation statements)

References 39 publications

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“…ABL1 (Abelson tyrosin protein kinase 1), located on 9q34, is a proto‐oncogene with cell cycle function involved in a variety of cellular processes, including cell division, adhesion and differentiation. It is known to be involved in myeloid and lymphoblastic leukemias as part of the Philadelphia chromosome …”

Section: Discussionmentioning

confidence: 99%

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases

Bekers

Groenen

Verdijk

et al. 2017

Genes Chromosomes & Cancer

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Soft tissue angiofibroma is rare and has characteristic histomorphological and genetic features. For diagnostic purposes, there are no specific antibodies available. Fourteen lesions (6 females, 8 males; age range 7-67 years) of the lower extremities (12) and trunk (2) were investigated by immunohistochemistry, including for the first time NCOA2. NCOA2 was also tested in a control group of other spindle cell lesions. The known fusion-genes (AHRR-NCOA2 and GTF2I-NCOA2) were examined using RT-PCR in order to evaluate their diagnostic value. Cases in which no fusion gene was detected were additionally analysed by RNA sequencing. All cases tested showed nuclear expression of NCOA2. However, this was not specific since other spindle cell neoplasms also expressed this marker in a high percentage of cases. Other variably positive markers were EMA, SMA, desmin and CD34. STAT6 was negative in the cases tested. By RT-PCR for the most frequently observed fusions, an AHRR-NCOA2 fusion transcript was found in 9/14 cases. GTF2I-NCOA2 was not detected in the remaining cases (n = 3). RNA sequencing revealed three additional positive cases; two harbored a AHRR-NCOA2 fusion and one case a novel GAB1-ABL1 fusion. Two cases failed molecular analysis due to poor RNA quality. In conclusion, the AHRR-NCOA2 fusion is a frequent finding in soft tissue angiofibroma, while GTF2I-NCOA2 seems to be a rare genetic event. For the first time, we report a GAB1-ABL1 fusion in a soft tissue angiofibroma of a child. Nuclear expression of NCOA2 is not discriminating when compared with other spindle cell neoplasms.

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Section: Discussionmentioning

confidence: 99%

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases

Bekers

Groenen

Verdijk

et al. 2017

Genes Chromosomes & Cancer

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“…Type I, II and IV TKIs, including imatinib, nilotinib, dasatinib, bosutinib and ponatinib, have shown activity against Bcr-Abl and have been approved by the FDA (Figure 2), and about 36 compounds have been patented during the last 8 years [9]. Nevertheless, imatinib has been shown to lose its effectiveness against CML in up to 30% of patients during their first five years on therapy [10].…”

Section: Figure 1 Schematic Representation Of the Moieties In Imatinmentioning

confidence: 99%

<strong>Docking studies of 1,5-disubtituted tetrazoles analogs of the anticancer drug imatinib as probable inhibitors of the ABL kinase and the T315I mutant kinase </strong>

Cortés-García

Suárez-Castro

Gamez-Montaño

et al. 2017

Proceedings of the 21st International Electronic Conference on Synthetic Organic Chemistry

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Abstract:A docking studies of a set of several 1,5-disubstituted tetrazoles (1,5-DS-T) compounds to find potential inhibitors of the Abelson tyrosine-protein kinase (ABL kinase) and the mutated ABL kinase T315I were conducted by using Lamarckian genetic algorithms as search algorithms in Autodock4. Bayesian calculations were performed, and specificity (Sp) and sensitivity (Se) values as well as positive predicted values (PPVs) and negative predicted values (NPVs) were calculated using a set of 99 active ligands and 385 decoys for ABL kinase from the DUD database. RMSD values were calculated between the X-ray crystallographically determined coordinates of the ligands in the complexes of ligand with the ABL kinase and with T315I ABL kinase resistant to imatinib. The predicted results showed the importance of the interactions of the protein with halogens present in some of these 1,5-DS-T ligands. In conclusion, the results suggest that eight novel 1,5-DS-T compounds were identified to be effective inhibitors of ABL kinase.

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“…Because this mutation occurs at the gatekeeper site and may cause steric hindrance precluding the access of the inhibitors to ATP-binding pocket [4], the discovery of potent Bcr-Abl inhibitors targeting T315I mutation would have important implications to treat the most clinically promising Abl T315I mutant therapies. Several new compounds, such as ponatinib [5] and rebastinib [6], have been studied clinically for CML patients harboring the Bcr-Abl T315I mutation, and it has shown that the Bcr-Abl inhibitors targeting the T315I mutant can inhibit the full range of Bcr-Abl kinase domain mutations as well as the wild-type kinase [7].…”

Section: Introductionmentioning

confidence: 99%

Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T315I Mutant Inhibitors

Lin

Tan

Zhou

et al. 2017

Chinese Journal of Chemical Physics

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Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T315I mutant, makes the search for new Abl T315I inhibitors a very interesting challenge in medicinal chemistry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T315I. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T315I activities were designed and presented to experimenters for reference.

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Bcr-Abl tyrosine kinase inhibitors: a patent review

Cited by 17 publications

References 39 publications

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases

Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases

<strong>Docking studies of 1,5-disubtituted tetrazoles analogs of the anticancer drug imatinib as probable inhibitors of the ABL kinase and the T315I mutant kinase </strong>

Binding Mechanism and Molecular Design of Benzimidazole/Benzothiazole Derivatives as Potent Abl T315I Mutant Inhibitors

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