scholarly journals Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling

2020 ◽  
Vol 15 (2) ◽  
pp. 396-415
Author(s):  
A.M. Anrdrianov ◽  
Yu.V. Kornoushenko ◽  
A.D. Karpenko ◽  
I.P. Bosko ◽  
Zh.V. Ignatovich ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Tyrosine Kinase ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Calculated Data ◽  
Protein Kinase Inhibitors ◽  
Modeling Tools ◽  
Abl Tyrosine Kinase ◽  
Anti Cancer ◽  
Derivatives Of

Discovery of the nature of inhibiting cancer processes by small organic molecules has changed the principles of the development of drug compounds for antitumor therapy. Recent achievements in this area are associated with the design of small-molecule protein kinase inhibitors, organic compounds exhibiting directed pathogenetic action. In this study, in silico design of 38 potential anti-cancer compounds with multikinase profile was carried out based on the derivatives of 2-arylaminopyrimidine. Evaluation of inhibitory activity potential of these compounds against the native and mutant (T315I) forms of Bcr-Abl tyrosine kinase, an enzyme that plays a key role in the pathogenesis of chronic myeloid leukemia characterized by uncontrolled growth myeloid cells in peripheral blood and bone marrow, was performed using molecular modeling tools. As a result, 5 top-ranking compounds that exhibit, according to the calculated data, a high-affinity binding to the native and mutant Bcr-Abl tyrosine kinase were identified. The designed compounds were shown to form good scaffolds for the development of novel potent antitumor drugs.

scholarly journals Specificity of dermatological adverse events of BCR-ABL tyrosine kinase inhibitors and their effect on quality of life of patients with chronic myeloid leukemia

2020 ◽  
pp. 72-76
Author(s):  
E. A. Shatokhina ◽  
A. G. Turkina ◽  
E. Yu. Chelysheva ◽  
O. A. Shukhov ◽  
A. N. Petrova ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Maculopapular Rash ◽  
Abl Tyrosine Kinase

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Prognostic factors of chronic myeloid leukaemia

2020 ◽  
pp. 63-78
Author(s):  
Michele Baccarani ◽  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Francesca Palandri ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukaemia ◽  
Risk Stratification ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
First Line ◽  
Abl Tyrosine Kinase ◽  
Baseline Characteristics ◽  
Kinase Domain Mutations

Two decades following the successful introduction of the ABL tyrosine kinase inhibitors in clinics for the treatment of patients with chronic myeloid leukaemia (CML), the principal objective of treatment in chronic phase (CP) is survival, preferably without life-long therapy. In tandem, the methodology and tools for assessing the prognosis of the newly diagnosed patient with CML in CP has evolved substantially. Prior to the era of tyrosine kinase inhibitors (TKIs), risk assessment depended more on the response to treatment than on baseline characteristics. The Sokal score, introduced in 1984, was the first one dividing patients into three risk categories based on a mathematical formula taking into account the patient’s age, and baseline characteristics like blast cell count, spleen size, and platelet count. This, and the several other subsequent risk stratification methods developed during the chemotherapy and interferon-alpha era, have remained useful in the first-line TKI treatment, and identifies a variable proportion of high-risk patients with lower response rates and worse outcomes. In second line, the most important risk factors are the absence of haematologic or cytogenetic response on first line, the presence of hematologic toxicity the development of additional cytogenetic abnormities (ACA), and the development of BCR-ABL1 kinase domain mutations. In this chapter, we address the prognosis of CML and the various methods for risk stratification.

scholarly journals Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

2019 ◽  
Vol 13 (4) ◽  
pp. 229-243 ◽  
Author(s):  
Katie Bechman ◽  
James B Galloway ◽  
Kevin L Winthrop
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Fungal Infections ◽  
Break Point ◽  
Pharmacokinetic Profile ◽  
Protein Kinase Inhibitors ◽  
Janus Kinase ◽  
The Impact

Abstract Purpose of Review This review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described. Recent Findings Protein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response. Summary The greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene–Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk.

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