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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/28096090/how-i-manage-ibrutinib-refractory-chronic-lymphocytic-leukemia
#1
Jennifer A Woyach
The introduction of the Bruton's Tyrosine Kinase inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia. Although responses have been durable in the majority of patients, relapses do occur, especially in the high risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes following ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28077600/ibrutinib-therapy-increases-t-cell-repertoire-diversity-in-patients-with-chronic-lymphocytic-leukemia
#2
Qingsong Yin, Mariela Sivina, Harlan Robins, Erik Yusko, Marissa Vignali, Susan O'Brien, Michael J Keating, Alessandra Ferrajoli, Zeev Estrov, Nitin Jain, William G Wierda, Jan A Burger
The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy...
January 11, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28073846/extended-treatment-with-single-agent-ibrutinib-at-the-420-mg-dose-leads-to-durable-responses-in-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma
#3
Steven E Coutré, Richard R Furman, Ian W Flinn, Jan A Burger, Kristie Blum, Jeff Sharman, Jeffrey Jones, William Wierda, Weiqiang Zhao, Nyla A Heerema, Amy J Johnson, Anh Tran, Cathy Zhou, Elizabeth Bilotti, Danelle F James, John C Byrd, Susan O'Brien
PURPOSE: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28062735/the-ability-of-btk-inhibitors-to-sequester-y551-and-prevent-phosphorylation-determines-potency-for-inhibition-of-fcr-but-not-b-cell-receptor-signaling
#4
Andrew T Bender, Anna Gardberg, Albertina Pereira, Theresa Johenson, Yin Wu, Roland Grenningloh, Jared Head, Federica Morandi, Philipp Haselmayer, Lesley Liu-Bujalski
Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B cell receptor (BCR), Fc receptors (FcR), and toll like receptors (TLRs). Btk has become an attractive drug target as Btk inhibition may provide significant efficacy by blocking multiple disease mechanisms simultaneously. Consequently, a large number of Btk inhibitors have been developed. The compounds have diverse binding modes and both reversible and irreversible inhibitors have been developed...
January 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28062113/indirect-treatment-comparisons-of-ibrutinib-versus-physician-s-choice-and-idelalisib-plus-ofatumumab-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#5
REVIEW
Sonja Sorensen, Mark Wildgust, Nishan Sengupta, Cristina Trambitas, Joris Diels, Suzy van Sanden, Yingxin Xu, Emily Dorman
PURPOSE: Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0...
January 3, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28060792/expression-of-x-linked-toll-like-receptor-4-signalling-genes-in-female-versus-male-neonates
#6
David N O'Driscoll, Chiara DeSanti, Paul J McKiernan, Victoria McEneaney, Eleanor J Molloy, Catherine M Greene
BACKGROUND: Male neonates display poorer disease prognosis and outcomes compared to females. Immune genes which exhibit higher expression in umbilical cord blood (UCB) of females may contribute to the female immune advantage during infection and inflammation. The aim of this study was to quantify expression of Toll-like receptor (TLR) 4 signalling genes encoded on the X-chromosome in UCB from term female versus male neonates. METHODS: UCB samples were collected from term neonates (n=26) born by elective Caesarean section and whole blood was collected from adults (n=20)...
January 6, 2017: Pediatric Research
https://www.readbyqxmd.com/read/28056160/discovery-of-a-potent-btk-inhibitor-with-a-novel-binding-mode-using-parallel-selections-with-a-dna-encoded-chemical-library
#7
John W Cuozzo, Paolo A Centrella, Diana Gikunju, Sevan Habeshian, Christopher D Hupp, Anthony D Keefe, Eric A Sigel, Holly H Soutter, Heather A Thomson, Ying Zhang, Matthew A Clark
We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA encoded library of over 110 million compounds using multiple parallel selection conditions including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building-block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP and another enriched at both high and low concentrations of BTK and was not competitive with ATP...
January 5, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28043164/current-treatment-options-and-investigational-drugs-for-waldenstrom-s-macroglobulinemia
#8
Maria Gavriatopoulou, Evangelos Terpos, Efstathios Kastritis, Meletios A Dimopoulos
Waldenström's Macroglobulinemia (WM) is a rare, indolent, incurable, low-grade B-cell lymphoplasmacytic neoplasm. This review article provides a modern clinical perspective of the individualized management of patients with symptomatic WM, in the context of the updated treatment guidelines and the currently available trial data. Areas covered: Rituximab-based regimens (such as the dexamethasone, rituximab and cyclophosphamide combination, DRC) are the most widely used in the management of both newly diagnosed and relapsed/refractory patients with WM...
January 3, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28035412/nicotinamide-phosphoribosyltransferase-inhibits-receptor-activator-of-nuclear-factor-%C3%AE%C2%BAb-ligand-induced-osteoclast-differentiation-in%C3%A2-vitro
#9
Jong Min Baek, Sung-Jun Ahn, Yoon-Hee Cheon, Myeung Su Lee, Jaemin Oh, Ju-Young Kim
The adipokine nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor or the insulin-mimetic hormone visfatin, has a crucial role in the conversion of nicotinamide to nicotinamide mononucleotide during biosynthesis of the coenzyme nicotinamide adenine dinucleotide. Previous reports have demonstrated the inhibitory effects of Nampt on osteoclast formation from human peripheral blood mononuclear cells and CD14+ monocytes. However, the effects of Nampt on bone marrow macrophage (BMM)‑derived osteoclastogenesis and its precise role in the process remain unclear...
February 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28034907/comparison-of-acalabrutinib-a-selective-bruton-tyrosine-kinase-inhibitor-with-ibrutinib-in-chronic-lymphocytic-leukemia-cells
#10
Viralkumar Patel, Kumudha Balakrishnan, Elena Bibikova, Mary Ayres, Michael J Keating, William Wierda, Varsha Gandhi
PURPOSE: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor designed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL...
December 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28034752/the-nlrp3-inflammasome-and-bruton-s-tyrosine-kinase-in-platelets-co-regulate-platelet-activation-aggregation-and-in-vitro-thrombus-formation
#11
Pranav Murthy, Filip Durco, Jennifer L Miller-Ocuin, Teiko Takedai, Shruthi Shankar, Xiaoyan Liang, Xiao Liu, Xiangdong Cui, Ulka Sachdev, Dominik Rath, Michael T Lotze, Herbert J Zeh, Meinrad Gawaz, Alexander N Weber, Sebastian Vogel
Cleavage of interleukin-1β (IL-1β) is a key inflammatory event in immune cells and platelets, which is mediated by nucleotide-binding domain leucine rich repeat containing protein (NLRP3)-dependent activation of caspase-1. In immune cells, NLRP3 and caspase-1 form inflammasome complexes with the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and bruton's tyrosine kinase (BTK). In platelets, however, the regulatory triggers and the functional effects of the NLRP3 inflammasome are unknown...
December 26, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28028621/expression-of-bruton-s-tyrosine-kinase-in-b-cell-neoplasms-evaluated-by-flow-cytometry
#12
Natália Aydos Marcondes, Flavo Beno Fernandes, Ana Paula Alegretti, Gustavo Adolpho Moreira Faulhaber
Bruton's tyrosine kinase (BTK) is a cytoplasmatic protein that is part of the B-cell antigen receptor signaling pathway. Our aim was to evaluate the expression of BTK in B-cell neoplasms and compare it to normal B-cell lymphocytes. After surface staining with CD19 and CD45, flow cytometry staining for intracellular BTK was performed in leukemic or mature B-cells from bone marrow or peripheral blood samples. No differences in BTK expression were identified between groups, or in comparison to control samples, there was no association between BTK expression and the clinical variables evaluated...
December 27, 2016: Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/28025004/mitigation-of-reactive-metabolite-formation-for-a-series-of-3-amino-2-pyridone-inhibitors-of-bruton-s-tyrosine-kinase-btk
#13
Yan Lou, Francisco Lopez, Yongying Jiang, Xiaochun Han, Chris Brotherton, Roland Billedeau, Steve Gabriel, Shelly Gleason, David M Goldstein, Ramona Hilgenkamp, Buelent Kocer, Lucja Orzechowski, Jenny Tan, Peter Wovkulich, Bo Wen, David Fry, Paola Di Lello, Lucy Chen, Fang-Jie Zhang, Jennifer Fretland, Anjali Nangia, Tian Yang, Timothy D Owens
Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e...
December 2, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28018445/a-novel-btk-gene-mutation-c-82delc-p-arg28-alafs-5-in-a-korean-family-with-x-linked-agammaglobulinemia
#14
Jeongeun Lee, Minhee Rhee, Taek Ki Min, Hae In Bang, Mi-Ae Jang, Eun-Suk Kang, Hee-Jin Kim, Hyeon-Jong Yang, Bok Yang Pyun
X-linked agammaglobulinemia (XLA) is a hereditary humoral immunodeficiency that results from Bruton's tyrosine kinase (BTK) gene mutations. These mutations cause defects in B-cell development, resulting in the virtual absence of these lymphocytes from the peripheral circulation. Consequently, this absence leads to a profound deficiency of lg all isotypes, and an increased susceptibility to encapsulated bacterial infections. A 15-month-old Korean boy presented with recurrent sinusitis and otitis media after 6 months of age, and had a family history of 2 maternal uncles with XLA...
November 2016: Korean Journal of Pediatrics
https://www.readbyqxmd.com/read/27994736/discovery-of-novel-bruton-s-tyrosine-kinase-btk-inhibitors-bearing-a-n-9-diphenyl-9h-purin-2-amine-scaffold
#15
Yang Ge, Yue Jin, Changyuan Wang, Jianbin Zhang, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Youwen Zhou, Xiaodong Ma
Based on the pyrimidine skeleton of EGFR(T790M) inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 μM...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27980745/a-case-of-new-onset-cardiomyopathy-and-ventricular-tachycardia-in-a-patient-receiving-ibrutinib-for-relapsed-mantle-cell-lymphoma
#16
Natalie Wallace, Ellice Wong, Dennis Cooper, Herta Chao
Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase, which is approved for use in chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Although ibrutinib has been linked to an increased incidence of atrial fibrillation, this is the first report of an association with nonischemic cardiomyopathy and ventricular arrhythmia.
December 2016: Clinical Case Reports
https://www.readbyqxmd.com/read/27960302/metabolically-labile-fumarate-esters-impart-kinetic-selectivity-to-irreversible-inhibitors
#17
Balyn W Zaro, Landon R Whitby, Kenneth M Lum, Benjamin F Cravatt
Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics...
December 14, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27956037/design-and-synthesis-of-phosphoryl-substituted-diphenylpyrimidines-pho-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-targeted-treatment-of-b-lymphoblastic-leukemia-cell-lines
#18
Yang Ge, Haijun Yang, Changyuan Wang, Qiang Meng, Lei Li, Huijun Sun, Yuhong Zhen, Kexin Liu, Yanxia Li, Xiaodong Ma
A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27941071/myd88-adapter-like-mal-is-phosphorylated-by-bruton-s-tyrosine-kinase-during-tlr2-and-tlr4-signal-transduction
#19
Pearl Gray, Aisling Dunne, Constantinos Brikos, Caroline A Jefferies, Sarah L Doyle, Luke A J O Neill
No abstract text is available yet for this article.
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27913510/frontline-therapy-and-role-of-high-dose-consolidation-in-mantle-cell-lymphoma
#20
Simon Rule
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. It is predominantly a disease of older individuals, with a median age at presentation of ∼70 years. For the majority of patients, the management revolves around immuno-chemotherapy often followed by maintenance rituximab, and at relapse, a range of options are available. For the younger patient, it is possible to be more intensive with therapy, consolidate responses with high-dose procedures, and in a few there might be the prospect of a cure...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
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