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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/28507715/a-quantitative-mechanistic-pk-pd-model-directly-connects-btk-target-engagement-and-in-vivo-efficacy
#1
Fereidoon Daryaee, Zhuo Zhang, Kayla R Gogarty, Yong Li, Jonathan Merino, Stewart L Fisher, Peter J Tonge
Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model that used drug-target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28503240/response-of-renal-cell-carcinoma-to-ibrutinib-a-bruton-tyrosine-kinase-inhibitor-in-a-patient-treated-for-chronic-lymphocytic-leukemia
#2
Gregory W Hosier, Naji J Touma
No abstract text is available yet for this article.
May 2017: Canadian Urological Association Journal, Journal de L'Association des Urologues du Canada
https://www.readbyqxmd.com/read/28487990/inhibition-of-btk-protects-lungs-from-trauma-hemorrhagic-shock-induced-injury-in-rats
#3
Xinwei Liu, Jingdong Zhang, Wenfeng Han, Yu Wang, Yunen Liu, Yubiao Zhang, Dapeng Zhou, Liangbi Xiang
The present study aimed to investigate the role of Bruton's tyrosine kinase (BTK) in the pathogenesis of lung injury induced by trauma‑hemorrhagic shock (THS), and to examine the pulmonary protective effects of BTK inhibition. Male Sprague‑Dawley rats were divided into four groups (n=12/group): i) A Sham group, which received surgery without induced trauma; ii) a THS‑induced injury group; iii) a THS‑induced injury group that also received treatment with the BTK inhibitor LFM‑A13 prior to trauma induction; and iv) a Sham group that was pretreated with LFM‑A13 prior to surgery but did not receive induced trauma...
May 9, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28480764/novel-agents-in-mantle-cell-lymphoma
#4
David Tucker, Simon Rule
Mantle cell lymphoma (MCL) usually takes an aggressive clinical course and carries a poor prognosis. Recently, progress has been made in the treatment of MCL including the development of a number of novel agents which target intracellular pathways and the extracellular microenvironment. These agents have transformed the landscape of available therapeutic options. Areas covered: The current literature on the novel agents which currently hold a licence for the treatment of MCL in the context of front-line therapy and in the relapsed/refractory setting is summarized...
May 17, 2017: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/28474336/comparative-genomic-expression-signatures-of-signal-transduction-pathways-and-targets-in-paediatric-burkitt-lymphoma-a-children-s-oncology-group-report
#5
Sanghoon Lee, Nancy S Day, Rodney R Miles, Sherrie L Perkins, Megan S Lim, Janet Ayello, Carmella van de Ven, Lauren Harrison, Nader K El-Mallawany, Stanton Goldman, Mitchell S Cairo
Burkitt lymphoma (BL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. Through the introduction of short intensive multi-agent chemoimmunotherapy, survival has improved significantly over the past 30 years. However, this successful approach is limited by significant chemotherapy-induced acute toxicity and risk of developing resistant disease, demonstrating the need to identify less toxic and targeted therapies. We analysed the comparative genomic signature and targetable signalling pathways in paediatric BL (PEBL) samples from the Children's Oncology Group study (ANHL01P1) by genomic profiling and selected genes were confirmed by quantitative real time polymerase chain reaction...
May 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28469834/ibrutinib-associated-skin-toxicity-a-case-of-maculopapular-rash-in-a-79-year-old-caucasian-male-patient-with-relapsed-waldenstrom-s-macroglobulinemia-and-review-of-the-literature
#6
Anders Bisgaard Jensen, Birgitte Stausbøl-Grøn, Rikke Riber-Hansen, Francesco d'Amore
Waldenstrom's macroglobulinamia (WM) is a rare malignant lymphoproliferative disorder, characterized by monoclonal IgM paraproteinemia and neoplastic proliferation of malignant lymphoplasmacytoid cells in the bone marrow. Traditionally, WM has been treated with modalities similar to those used in the management of other indolent lymphomas. Just recently, based on impressive clinical trial results in heavily pretreated WM patients, a new Bruton Tyrosine Kinase-inhibitor, Ibrutinib, has been approved for the treatment of this disorder...
March 13, 2017: Dermatology Reports
https://www.readbyqxmd.com/read/28468967/high-syk-expression-drives-constitutive-activation-of-cd21-low-b-cells
#7
Baerbel Keller, Ina Stumpf, Valentina Strohmeier, Susanne Usadel, Els Verhoeyen, Hermann Eibel, Klaus Warnatz
Human CD21(low) B cells present with an activated phenotype and accumulate in distinct disorders connected with chronic immune stimulation. Signaling studies had revealed an increased basal phosphorylation of spleen tyrosine kinase (SYK) and phospholipase Cγ2. Additional BCR stimulation of these constitutively active cells, however, led to reduced activation of these signaling molecules and subsequently NF-κB and Ca(2+) activation. In this article, we demonstrate that high SYK expression is a common feature of CD21(low) B cells independent of the underlying disorder, and that this high expression is sufficient to drive constitutive phosphorylation of SYK and its immediate targets Bruton's tyrosine kinase and phospholipase Cγ2...
May 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28451787/future-therapeutic-targets-in-rheumatoid-arthritis
#8
REVIEW
Tommy Tsang Cheung, Iain B McInnes
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon...
April 27, 2017: Seminars in Immunopathology
https://www.readbyqxmd.com/read/28446319/-progress-on-treatment-of-splenic-marginal-zone-lymphoma-review
#9
Ling Wu, Chen Tian, Yi-Zhuo Zhang
Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell non-Hodgkin's lymphoma. The clinical features of SMZL are splenomegaly, lymphocytosis and cytopenia in peripheral blood. Immunopheno-typically, the neoplastic cells are typically positive for CD45, CD20, CD79a, PAX5, IgD, BCL-2. The previous common used treatment is splenectomy and chemotherapy. Nowadays, rituximab-based chemotherapy regimens has improved the curative effect dramaticlly. IFN-α with or without ribavirin can be used to treat the patients with HCV infection...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28439883/an-update-for-richter-syndrome-new-directions-and-developments
#10
REVIEW
Toby A Eyre, Anna Schuh
High-grade transformation of chronic lymphocytic leukaemia [Richter syndrome (RS)] is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS is a chemotherapy-resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28432946/design-and-synthesis-of-sulfonamide-substituted-diphenylpyrimidines-sfa-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-cell-lymphoblastic-leukemia
#11
He Liu, Menghua Qu, Lina Xu, Xu Han, Changyuan Wang, Xiaohong Shu, Jihong Yao, Kexin Liu, Jinyong Peng, Yanxia Li, Xiaodong Ma
A new series of diphenylpyrimidine derivatives (SFA-DPPYs) were synthesized by introducing a functional sulfonamide into the C-2 aniline moiety of pyrimidine template, and then were biologically evaluated as potent Bruton's tyrosine kinase (BTK) inhibitors. Among these molecules, inhibitors 10c, 10i, 10j and 10k displayed high potency against the BTK enzyme, with IC50 values of 1.18 nM, 0.92 nM, 0.42 nM and 1.05 nM, respectively. In particular, compound 10c could remarkably inhibit the proliferation of the B lymphoma cell lines at concentrations of 6...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28428442/combination-of-ibrutinib-and-abt-199-in-diffuse-large-b-cell-lymphoma-and-follicular-lymphoma
#12
Hsu-Ping Kuo, Scott A Ezell, Karl J Schweighofer, Leo Wk Cheung, Sidney Hsieh, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Ssucheng J Hsu, Chun-Te Chen, Darrin M Beaupre, Matthias Versele, Betty Y Chang
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton's tyrosine kinase (BTK)-mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance...
April 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28424405/the-bruton-s-tyrosine-kinase-inhibitor-ibrutinib-exerts-immunomodulatory-effects-through-regulation-of-tumor-infiltrating-macrophages
#13
Lingyan Ping, Ning Ding, Yunfei Shi, Lixia Feng, Jiao Li, Yalu Liu, Yufu Lin, Cunzhen Shi, Xing Wang, Zhengying Pan, Yuqin Song, Jun Zhu
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-cell lymphomas through crosstalk mediated by secreted cytokines and chemokines. Because Btk has been implicated in Toll-like receptor (TLR) signaling pathways that regulate macrophage activation and production of proinflammatory cytokines, we investigated the immunomodulatory effects of Btk inhibitor on macrophages...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418267/btk-c481s-mediated-resistance-to-ibrutinib-in-chronic-lymphocytic-leukemia
#14
Jennifer A Woyach, Amy S Ruppert, Daphne Guinn, Amy Lehman, James S Blachly, Arletta Lozanski, Nyla A Heerema, Weiqiang Zhao, Joshua Coleman, Daniel Jones, Lynne Abruzzo, Amber Gordon, Rose Mantel, Lisa L Smith, Samantha McWhorter, Melanie Davis, Tzyy-Jye Doong, Fan Ny, Margaret Lucas, Weihong Chase, Jeffrey A Jones, Joseph M Flynn, Kami Maddocks, Kerry Rogers, Samantha Jaglowski, Leslie A Andritsos, Farrukh T Awan, Kristie A Blum, Michael R Grever, Gerard Lozanski, Amy J Johnson, John C Byrd
Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population...
February 13, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28416797/unification-of-de-novo-and-acquired-ibrutinib-resistance-in-mantle-cell-lymphoma
#15
Xiaohong Zhao, Tint Lwin, Ariosto Silva, Bijal Shah, Jiangchuan Tao, Bin Fang, Liang Zhang, Kai Fu, Chengfeng Bi, Jiannong Li, Huijuan Jiang, Mark B Meads, Timothy Jacobson, Maria Silva, Allison Distler, Lancia Darville, Ling Zhang, Ying Han, Dmitri Rebatchouk, Maurizio Di Liberto, Lynn C Moscinski, John M Koomen, William S Dalton, Kenneth H Shain, Michael Wang, Eduardo Sotomayor, Jianguo Tao
The novel Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated high response rates in B-cell lymphomas; however, a growing number of ibrutinib-treated patients relapse with resistance and fulminant progression. Using chemical proteomics and an organotypic cell-based drug screening assay, we determine the functional role of the tumour microenvironment (TME) in ibrutinib activity and acquired ibrutinib resistance. We demonstrate that MCL cells develop ibrutinib resistance through evolutionary processes driven by dynamic feedback between MCL cells and TME, leading to kinome adaptive reprogramming, bypassing the effect of ibrutinib and reciprocal activation of PI3K-AKT-mTOR and integrin-β1 signalling...
April 18, 2017: Nature Communications
https://www.readbyqxmd.com/read/28416773/changes-in-t-cell-subpopulations-and-cytokine-network-during-early-period-of-ibrutinib-therapy-in-chronic-lymphocytic-leukemia-patients-the-significant-decrease-in-t-regulatory-cells-number
#16
Monika Podhorecka, Aneta Goracy, Agnieszka Szymczyk, Malgorzata Kowal, Blanca Ibanez, Olga Jankowska-Lecka, Arkadiusz Macheta, Aleksandra Nowaczynska, Elzbieta Drab-Urbanek, Sylwia Chocholska, Dariusz Jawniak, Marek Hus
B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408842/spotlight-on-ibrutinib-and-its-potential-in-frontline-treatment-of-chronic-lymphocytic-leukemia
#17
REVIEW
Maliha Khan, Jamie L Gibbons, Alessandra Ferrajoli
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the adult population. Current efforts are focused on better understanding the intricate pathophysiology of the disease to develop successful targeted therapies. Ibrutinib is emerging as an important agent in this new age of targeted treatment for CLL. As a Bruton's tyrosine kinase inhibitor, it blocks the signaling pathway that malignant B-lymphocytes need for growth and maturation. Ibrutinib's role in therapy was further expanded recently when the US Food and Drug Administration approved its use in both frontline and salvage treatment for patients with CLL...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28405610/btk-specific-inhibition-blocks-pathogenic-plasma-cell-signatures-and-myeloid-cell-associated-damage-in-ifn%C3%AE-driven-lupus-nephritis
#18
Arna Katewa, Yugang Wang, Jason A Hackney, Tao Huang, Eric Suto, Nandhini Ramamoorthi, Cary D Austin, Meire Bremer, Jacob Zhi Chen, James J Crawford, Kevin S Currie, Peter Blomgren, Jason DeVoss, Julie A DiPaolo, Jonathan Hau, Adam Johnson, Justin Lesch, Laura E DeForge, Zhonghua Lin, Marya Liimatta, Joseph W Lubach, Sami McVay, Zora Modrusan, Allen Nguyen, Chungkee Poon, Jianyong Wang, Lichuan Liu, Wyne P Lee, Harvey Wong, Wendy B Young, Michael J Townsend, Karin Reif
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma cell generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes and promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe the characterization of a highly selective reversible Btk inhibitor, G-744. G-744 is efficacious, and superior to blocking BAFF and Syk, in ameliorating severe lupus nephritis in both spontaneous and IFNα-accelerated lupus in NZB/W_F1 mice in therapeutic regimens...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28391340/targeting-the-tyrosine-kinase-signalling-pathways-for-treatment-of-immune-mediated-glomerulonephritis-from-bench-to-bedside-and-beyond
#19
Terry King-Wing Ma, Stephen P McAdoo, Frederick Wai Keung Tam
Glomerulonephritis (GN) affects patients of all ages and is an important cause of morbidity and mortality. Non-selective immunosuppressive drugs have been used in immune-mediated GN but often result in systemic side effects and occasionally fatal infective complications. There is increasing evidence from both preclinical and clinical studies that abnormal activation of receptor and non-receptor tyrosine kinase signalling pathways are implicated in the pathogenesis of immune-mediated GN. Activation of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and discoidin domain receptor 1 (DDR1) have been demonstrated in anti-GBM disease...
January 1, 2017: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/28389390/ibrutinib-a-btk-inhibitor-used-for-treatment-of-lymphoproliferative-disorders-eliminates-both-aeroallergen-skin-test-and-basophil-activation-test-reactivity
#20
Jennifer A Regan, Yun Cao, Melanie C Dispenza, Shuo Ma, Leo I Gordon, Adam M Petrich, Bruce S Bochner
Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was shown to eliminate skin test reactivity in vivo and IgE-dependent basophil activation testing ex vivo. Blockade of the BTK pathway may represent a novel therapeutic strategy for the effective reduction of allergic reactivity.
April 4, 2017: Journal of Allergy and Clinical Immunology
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