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https://www.readbyqxmd.com/read/27913183/nmr-strategies-to-support-medicinal-chemistry-workflows-for-primary-structure-determination
#1
Paul Oguadinma, Francois Bilodeau, Steven R LaPlante
Central to drug discovery is the correct characterization of the primary structures of compounds. In general, medicinal chemists make great synthetic and characterization efforts to deliver the intended compounds. However, there are occasions which incorrect compounds are presented, such as those reported for Bosutinib and TIC10. This may be due to a variety of reasons such as uncontrolled reaction schemes, reliance on limited characterization techniques (LC-MS and/or 1D 1H NMR spectra), or even the lack of availability or knowledge of characterization strategies...
November 24, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27903968/novel-src-abl-tyrosine-kinase-inhibitor-bosutinib-suppresses-neuroblastoma-growth-via-inhibiting-src-abl-signaling
#2
Shayahati Bieerkehazhi, Zhenghu Chen, Yanling Zhao, Yang Yu, Huiyuan Zhang, Sanjeev A Vasudevan, Sarah E Woodfield, Ling Tao, Joanna S Yi, Jodi A Muscal, Jonathan C Pang, Shan Guan, Hong Zhang, Jed G Nuchtern, Hui Li, Huiwu Li, Jianhua Yang
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27901368/second-line-small-molecule-therapy-options-for-treating-chronic-myeloid-leukemia
#3
Matteo Molica, Fulvio Massaro, Massimo Breccia
Approximately 33% of chronic myeloid leukemia (CML) patients discontinue treatment with imatinib in the long-term due to resistance and/or intolerance. Second-generation tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) have added complexity to the treatment paradigm for this disease. Areas covered: Second generation TKIs, approved as second-line treatment in all phases of the disease, are highly effective in patients resistant to and/or intolerant to imatinib and are extremely active against all the resistant BCR-ABL1 mutations, with the exception of T3151...
November 30, 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27861317/development-and-validation-of-a-simultaneous-quantification-method-of-fourteen-tyrosine-kinase-inhibitors-in-human-plasma-using-lc-ms-ms
#4
Huu-Hien Huynh, Claire Pressiat, Hélène Sauvageon, Isabelle Madelaine, Patricia Maslanka, Céleste Lebbé, Catherine Thieblemont, Lauriane Goldwirt, Samia Mourah
BACKGROUND: A sensitive LC-MS/MS method for the analysis in a small volume of plasma of 14 tyrosine kinase inhibitors (TKIs) currently used (imatinib, dasatinib, ibrutinib, ponatinib, trametinib, sunitinib, cobimetinib, dabrafenib, erlotinib, lapatinib, nilotinib, bosutinib, sorafenib, and vemurafenib) has been developed and validated. This multi-analyte LC-MS/MS assay is of interest for anticancer drug combination therapy. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using a UPLC system coupled with MS/MS in a positive ionization mode...
November 16, 2016: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27858461/how-could-patient-reported-outcomes-improve-patient-management-in-chronic-myeloid-leukemia
#5
Federico De Marchi, Marta Medeot, Renato Fanin, Mario Tiribelli
Patients reported outcome (PRO) are still under-used in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), though data on the correlation between quality of life (QoL) and therapeutic efficacy are increasingly known. Chronic low-grade toxicities can reduce patient's QoL and negatively impact on adherence. Areas covered: This review will focus on the role of QoL questionnaires in patients with CML, receiving imatinib or newer TKIs (dasatinib, nilotinib, bosutinib, ponatinib)...
November 30, 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27842767/drug-hepatotoxicity-newer-agents
#6
REVIEW
Chalermrat Bunchorntavakul, K Rajender Reddy
Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents...
February 2017: Clinics in Liver Disease
https://www.readbyqxmd.com/read/27777385/decreased-mtor-signalling-reduces-mitochondrial-ros-in-brain-via-accumulation-of-the-telomerase-protein-tert-within-mitochondria
#7
Satomi Miwa, Rafal Czapiewski, Tengfei Wan, Amy Bell, Kirsten N Hill, Thomas von Zglinicki, Gabriele Saretzki
Telomerase in its canonical function maintains telomeres in dividing cells. In addition, the telomerase protein TERT has non-telomeric functions such as shuttling to mitochondria resulting in a decreased oxidative stress, DNA damage and apoptosis. TERT protein persists in adult neurons and can co-localise to mitochondria under various stress conditions. We show here that TERT expression decreased in mouse brain during aging while release of reactive oxygen species (ROS) from the mitochondrial electron transport chain increased...
October 22, 2016: Aging
https://www.readbyqxmd.com/read/27718000/effect-of-aprepitant-a-moderate-cyp3a4-inhibitor-on-bosutinib-exposure-in-healthy-subjects
#8
Poe-Hirr Hsyu, Daniela Soriano Pignataro, Kyle Matschke
PURPOSE: Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg...
October 7, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27717999/effect-of-bosutinib-on-the-absorption-of-dabigatran-etexilate-mesylate-a-p-glycoprotein-substrate-in-healthy-subjects
#9
Poe-Hirr Hsyu, Daniela Soriano Pignataro, Kyle Matschke
PURPOSE: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated. METHODS: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally)...
October 7, 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27713843/tyrosine-kinase-inhibitors-for-the-treatment-of-chronic-phase-chronic-myeloid-leukemia-long-term-patient-care-and-management
#10
Stephanie Bauer, Susan Buchanan, Irene Ryan
Several tyrosine kinase inhibitors (TKIs) are now approved for the treatment of chronic myeloid leukemia in chronic phase. The efficacy of these drugs has been repeatedly demonstrated, as has their tolerability in most patients. However, late and chronic toxicities become an important issue for many patients facing long-term TKI exposure. For patients on long-term imatinib, gastrointestinal events, fluid retention, muscle cramps, fatigue, and hepatotoxicity are among the most common and most clinically relevant adverse events (AEs)...
January 2016: Journal of the Advanced Practitioner in Oncology
https://www.readbyqxmd.com/read/27696211/the-myocyte-damaging-effects-of-the-bcr-abl1-targeted-tyrosine-kinase-inhibitors-increase-with-potency-and-decrease-with-specificity
#11
Brian B Hasinoff, Daywin Patel, Xing Wu
Five clinically approved BCR-ABL1-targeted tyrosine kinase inhibitors (bosutinib, dasatinib, imatinib, nilotinib, and ponatinib) used for treating chronic myelogenous leukemia have been studied in a neonatal rat myocyte model for their relative ability to induce myocyte damage. This was done in order to determine if kinase inhibitor-induced myocyte damage was a consequence of inhibiting ABL1 (on-target effects), or due to a lack of kinase selectivity (off-target effects) since previous studies have come up with conflicting conclusions about whether imatinib-induced cardiotoxicity results directly from inhibition of ABL1...
September 30, 2016: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/27562641/rationale-and-motivating-factors-for-treatment-free-remission-in-chronic-myeloid-leukemia
#12
Lauren Caldemeyer, Luke P Akard
With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses...
December 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27560448/first-line-treatment-with-newer-tyrosine-kinase-inhibitors-in-chronic-myeloid-leukemia-associated-with-deep-and-durable-molecular-response-systematic-review-and-meta-analysis
#13
Ronit Gurion, Pia Raanani, Liat Vidal, Avi Leader, Anat Gafter-Gvili
BACKGROUND: The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib)...
September 2016: Acta Oncologica
https://www.readbyqxmd.com/read/27531525/long-term-bosutinib-for-chronic-phase-chronic-myeloid-leukemia-after-failure-of-imatinib-plus-dasatinib-and-or-nilotinib
#14
Jorge E Cortes, Hanna J Khoury, Hagop M Kantarjian, Jeff H Lipton, Dong-Wook Kim, Philippe Schafhausen, Ewa Matczak, Eric Leip, Kay Noonan, Tim H Brümmendorf, Carlo Gambacorti-Passerini
Bosutinib is an Src/Abl tyrosine kinase inhibitor (TKI) indicated for adults with Ph+ chronic myeloid leukemia (CML) resistant/intolerant to prior TKIs. This long-term update of an ongoing phase 1/2 study evaluated the efficacy and safety of third-/fourth-line bosutinib in adults with chronic phase (CP) CML. Median durations of treatment and follow-up were 8.6 (range, 0.2-87.7) months and 32.7 (0.3-93.3) months, respectively. Cumulative confirmed complete hematologic response (cCHR) and major cytogenetic response (MCyR) rates were 74% (95% CI, 65-81%) and 40% (31-50%), respectively; Kaplan-Meier (K-M) probability of maintaining cCHR or MCyR at 4 years was 63% (95% CI, 50-73%) and 69% (52-81%)...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27507246/tyrosine-kinase-inhibition-reverses-tdp-43-effects-on-synaptic-protein-expression-astrocytic-function-and-amino-acid-dis-homeostasis
#15
Lanier Heyburn, Michaeline L Hebron, Jacqueline Smith, Charisse Winston, John Bechara, Zhaoxia Li, Irina Lonskaya, Mark P Burns, Brent T Harris, Charbel E-H Moussa
The trans-activating response of DNA/RNA-binding protein (TDP)-43 pathology is associated with many neurodegenerative diseases via unknown mechanisms. Here, we use a transgenic mouse model over-expressing human wild-type neuronal TDP-43 to study the effects of TDP-43 pathology on glutamate metabolism and synaptic function. We found that neuronal TDP-43 over-expression affects synaptic protein expression, including Synapsin I, and alters surrounding astrocytic function. TDP-43 over-expression is associated with an increase in glutamate and γ-amino butyric acid and reduction of glutamine and aspartate levels, indicating impairment of presynaptic terminal...
November 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27491651/combination-of-in-silico-analysis-and-in-vitro-assay-to-investigate-drug-response-to-human-epidermal-growth-factor-receptor-2-mutations-in-lung-cancer
#16
Xiyan Yu, Tong Wang, Ying Lou, Yanwen Li
The epidermal growth factor receptor 2 (HER2) has been established as an important target of HER2-positive lung cancer, but somatic mutations in HER2 kinase domain are frequently observed that may cause drug resistance and sensitivity for tyrosine kinase inhibitors (TKIs). In this study, the response profile of 14 small-molecule TKIs upon 11 clinical HER2 mutations was investigated systematically using a synthetic strategy that integrated in silico analysis and in vitro assay to explore the structural basis, energetic property and biological implication underlying the intermolecular interactions of TKIs with wild-type and variant HER2...
January 2016: Molecular Informatics
https://www.readbyqxmd.com/read/27432881/selective-inhibition-of-human-equilibrative-and-concentrative-nucleoside-transporters-by-bcr-abl-kinase-inhibitors-identification-of-key-hent1-amino-acid-residues-for-interaction-with-bcr-abl-kinase-inhibitors
#17
Vijaya L Damaraju, Dwayne Weber, Michelle Kuzma, Carol E Cass, Michael B Sawyer
Human nucleoside transporters (hNTs) mediate cellular influx of anticancer nucleoside drugs, including cytarabine, cladribine, and fludarabine. BCR-ABL tyrosine kinase inhibitors (TKIs) imatinib and dasatinib inhibit fludarabine and cytarabine uptake. We assessed interactions of bosutinib, dasatinib, imatinib, nilotinib, and ponatinib with recombinant hNTs (hENT1, 2; hCNT1, -2, and -3) produced individually in yeast Saccharomyces cerevisiae Nilotinib inhibited hENT1-mediated uridine transport most potently (IC50 value, 0...
September 2, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27358479/the-src-kinases-hck-fgr-and-lyn-activate-arg-to-facilitate-igg-mediated-phagocytosis-and-leishmania-infection
#18
Dawn M Wetzel, Emma L Rhodes, Shaoguang Li, Diane McMahon-Pratt, Anthony J Koleske
Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood...
August 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27307150/cellular-and-molecular-networks-in-chronic-myeloid-leukemia-the-leukemic-stem-progenitor-and-stromal-cell-interplay
#19
Danilo Perrotti, Giovannino Silvestri, Lorenzo Stramucci, Justine Yu, Rossana Trotta
The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e. dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event; however, disease progression still occurs in those patients who are refractory, not compliant with TKI therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCR-ABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression...
June 14, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27218866/the-treatment-of-cml-at-an-environment-with-limited-resources
#20
David Gómez-Almaguer, Olga G Cantú-Rodríguez, Cesar H Gutiérrez-Aguirre, Guillermo J Ruiz-Argüelles
OBJECTIVES: This article reviews clinical experiences in the treatment of chronic myeloid leukemia (CML) in an environment of limited resources. METHODS: We reviewed recent publications on Pub med and abstracts from mayor congresses relevant to the disease. RESULTS: CML is a hematological neoplasm observed more frequently in adults, regardless of their socioeconomic status. Until recently, available treatments improved patients' quality of life but did not modify survival...
May 24, 2016: Hematology (Amsterdam, Netherlands)
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