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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/27913510/frontline-therapy-and-role-of-high-dose-consolidation-in-mantle-cell-lymphoma
#1
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
https://www.readbyqxmd.com/read/27912175/structural-optimization-of-diphenylpyrimidine-derivatives-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-leukemia-cell-lines
#2
Dan Zhao, Shanshan Huang, Menghua Qu, Changyuan Wang, Zhihao Liu, Zhen Li, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma, Xiaohong Shu
A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50 values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27909342/ristocetin-induced-platelet-aggregation-for-monitoring-of-bleeding-tendency-in-cll-treated-with-ibrutinib
#3
L Kazianka, C Drucker, C Skrabs, W Thomas, T Melchardt, S Struve, M Bergmann, P B Staber, E Porpaczy, C Einberger, M Heinz, A Hauswirth, M Raderer, I Pabinger, R Thalhammer, A Egle, C-M Wendtner, G Follows, G Hoermann, P Quehenberger, B Jilma, U Jaeger
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27904766/the-role-of-pim1-in-the-ibrutinib-resistant-abc-subtype-of-diffuse-large-b-cell-lymphoma
#4
Hsu-Ping Kuo, Scott A Ezell, Sidney Hsieh, Karl J Schweighofer, Leo Wk Cheung, Shiquan Wu, Mutiah Apatira, Mint Sirisawad, Karl Eckert, Yu Liang, Jeff Hsu, Chun-Te Chen, Darrin Beaupre, Betty Y Chang
Diffuse large B cell lymphoma (DLBCL) is a heterogeneous lymphoma and the most common subtype of non-Hodgkin lymphoma, accounting for roughly 30% of newly diagnosed cases in the United States. DLBCL can be separated into the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, with distinct gene expression profiles, oncogenic aberrations, and clinical outcomes. ABC-DLBCL is characterized by chronically active B-cell receptor (BCR) signaling that can be modulated by Bruton's tyrosine kinase (BTK) activity...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27904138/cirmtuzumab-inhibits-wnt5a-induced-rac1-activation-in-chronic-lymphocytic-leukemia-treated-with-ibrutinib
#5
J Yu, L Chen, B Cui, C Wu, M Y Choi, Y Chen, L Zhang, L Z Rassenti, G F Widhopf, T J Kipps
Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival...
December 1, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#6
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27867589/bruton-s-agammaglobulinemia-in-an-adult-male-due-to-a-novel-mutation-a-case-report
#7
Yuanda Xu, Qi Qing, Xuesong Liu, Sibei Chen, Ziyi Chen, Xuefeng Niu, Yaxia Tan, Weiqun He, Xiaoqing Liu, Yimin Li, Rongchang Chen, Ling Chen
X-linked agammaglobulinemia (XLA) is caused by mutation in the gene coding for Bruton's tyrosine kinase (BTK), which impairs peripheral B cell maturation and hypogammaglobulinemia. In this report, we present a case of XLA in a 22-year-old adult male. Genetic testing revealed a novel mutation located at the conserved region (c.383T>C). The patient had a history of recurrent respiratory tract infection which eventually progressed to chronic type II respiratory failure. Several pathogenic bacteria were isolated on culture of respiratory secretions obtained on bronchoscopy...
October 2016: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/27854102/the-next-generation-of-targeted-molecules-for-the-treatment-of-chronic-lymphocytic-leukemia
#8
REVIEW
Deepa Jeyakumar, Susan O'Brien
With the recent approval of several new targeted therapies for chronic lymphocytic leukemia (CLL), there are now multiple options for its treatment. Inhibitors of Bruton tyrosine kinase (with ibrutinib being the first-in-class US Food and Drug Administration-approved agent) and phosphoinositide 3-kinase (with idelalisib as the first-in-class approved agent) are promising because they are generally well tolerated and highly effective against this malignancy. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and subsequent infections) associated with chemoimmunotherapy...
November 15, 2016: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/27854034/efficient-preparation-of-s-n-boc-3-hydroxylpiperidine-through-bioreduction-by-a-thermostable-aldo-ketoreductase
#9
Mengyan He, Shuo Zhou, Maolin Cui, Xiaolu Jin, Dunyue Lai, Shuangling Zhang, Zhiguo Wang, Zhenming Chen
(S)-N-Boc-3-hydroxypiperidine ((S)-NBHP) is a key pharmaceutical intermediate and the chiral source in synthesizing Imbruvica, which is a newly approved drug in lymphoma therapy by targeting Bruton's tyrosine kinase (BTK). Current chemical synthesis of (S)-NBHP suffered from the need of noble metal catalyst and low yield. The single reported bioconversion of (S)-NBHP was achieved by using recombinant ketoreductase, but enzyme sequence was kept confidential and the catalytic process suffered from the thermodeactivation and substrate inhibition...
November 16, 2016: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/27825467/future-therapeutic-options-for-patients-with-waldenstr%C3%A3-m-macroglobulinemia
#10
REVIEW
Jorge J Castillo, Zachary R Hunter, Guang Yang, Kimon Argyropoulos, M Lia Palomba, Steven P Treon
Waldenström macroglobulinemia (WM) is a rare lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells. Although WM patients can experience prolonged remissions, the disease invariably recurs. Therefore, novel treatments associated with higher success rates and lower toxicity profiles are needed. The discovery of recurrent mutations in the MYD88 and CXCR4 genes has unraveled potential therapeutic targets in WM patients. As a result of these findings and based on the design and execution of a prospective clinical trial, the FDA granted approval to ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, to treat patients with symptomatic WM...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27825463/preclinical-models-of-waldenstr%C3%A3-m-s-macroglobulinemia-and-drug-resistance
#11
REVIEW
Sikander Ailawadhi, Aneel Paulus, Asher Chanan-Khan
Newer therapeutic strategies are emerging in Waldenström's Macroglobulinemia (WM), which has traditionally been an orphan disease diagnosis. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was FDA-approved in 2015 as the first ever drug for the treatment of WM. This being a targeted therapy, has given rise to increased research into novel agents and pathways that can be exploited for clinical benefit in WM. In order to understand the underlying mechanisms of disease behavior as well as to test the benefit of various drugs, appropriate preclinical models are required...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27821712/btk-small-molecule-inhibitors-induce-a-distinct-pancreatic-toxicity-in-rats
#12
Rebecca I Erickson, Leah K Schutt, Jacqueline Tarrant, Michelle McDowell, Lichuan Liu, Adam R Johnson, Sock-Cheng Lewin-Koh, Maj Hedehus, Jed Ross, Richard A D Carano, Karin Staflin, Fiona Zhong, James Crawford, Shelly Zhong, Karin Reif, Arna Katewa, Harvey Wong, Wendy Young, Donna Dambach, Dinah Misner
Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematological cancers and autoimmune diseases. GDC-0853 is a selective and reversible oral small molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation...
November 7, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27820779/bruton-s-tyrosine-kinase-inhibition-attenuates-liver-damage-in-a-mouse-warm-ischemia-and-reperfusion-model
#13
T Palumbo, K Nakamura, C Lassman, Y Kidani, S J Bensinger, R W Busuttil, J W Kupiec-Weglinski, A Zarrinpar
BACKGROUND: Bruton's tyrosine kinase (Btk) is a central player in multiple signaling pathways of lymphoid and myeloid cells. Myeloid cells are crucial early effectors in organ ischemia/reperfusion injury (IRI). BTKB66 is a selective, irreversible inhibitor of Btk. In this study, we hypothesized that Btk inhibition would reduce hepatocellular injury in a murine model of liver warm hepatic ischemia and reperfusion. METHODS: First, BTKB66 was tested in in vitro models of LPS-mediated neutrophil and macrophage activation...
November 3, 2016: Transplantation
https://www.readbyqxmd.com/read/27819687/impact-of-drug-development-on-the-use-of-stem-cell-transplantation-a-report-by-the-european-society-for-blood-and-marrow-transplantation-ebmt
#14
J R Passweg, H Baldomero, P Bader, C Bonini, S Cesaro, P Dreger, R F Duarte, C Dufour, J Kuball, D Farge-Bancel, A Gennery, N Kröger, F Lanza, A Nagler, A Sureda, M Mohty
Hematopoietic stem cell transplantation (HSCT) is used with increasing frequency in Europe with 40 000 transplants reported in 2014. Transplant-related mortality remains high in allogeneic HSCT (10-20%); high-dose chemotherapy is toxic and demanding for patients. Drug development is accelerating and with limited toxicity of some targeted drugs may replace HSCT, whereas others may function as a 'bridge to transplant'. We analyzed HSCT reported to the activity survey for selected diseases in which major advances in drug development have been made...
November 7, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27802969/ibrutinib-efficacy-and-tolerability-in-patients-with-relapsed-chronic-lymphocytic-leukemia-following-allogeneic-hct
#15
Christine E Ryan, Bita Sahaf, Aaron C Logan, Susan O'Brien, John C Byrd, Peter Hillmen, Jennifer R Brown, Martin J S Dyer, Anthony R Mato, Michael J Keating, Samantha Jaglowski, Fong Clow, Andrew R Rezvani, Lori Styles, Steven E Coutre, David B Miklos
Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplantation who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87...
November 1, 2016: Blood
https://www.readbyqxmd.com/read/27793942/a-novel-aziridine-based-bruton-s-tyrosine-kinase-inhibitor-induces-apoptosis-through-down-regulation-of-p65-rela-phosphorylation-on-serine-536-and-erk1-2-in-mantle-cell-lymphoma
#16
Nadezhda Romanchikova, Arnis Strods, Julija Strazdina, Boriss Strumfs, Peteris Trapencieris
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma characterized by hyperactive neoplastic B-cells and extended tumor cell survival. Bruton's tyrosine kinase (BTK), a crucial kinase in the B-cell antigen receptor signaling pathway, has emerged as a novel target of MCL therapy. A novel BTK-targeting inhibitor, JuSt-23F was prepared. MATERIALS AND METHODS: The WST-8 assay was used to determine cytotoxicity and half-maximal inhibitory concentration (IC50) values for JuSt-23F against the MCL cell lines Mino and Maver-1...
November 2016: Anticancer Research
https://www.readbyqxmd.com/read/27793034/therapeutic-efficacy-of-the-bromodomain-inhibitor-otx015-mk-8628-in-alk-positive-anaplastic-large-cell-lymphoma-an-alternative-modality-to-overcome-resistant-phenotypes
#17
Michela Boi, Maria Todaro, Valentina Vurchio, Shao Ning Yang, John Moon, Ivo Kwee, Andrea Rinaldi, Heng Pan, Ramona Crescenzo, Mangeng Cheng, Leandro Cerchietti, Olivier Elemento, Maria E Riveiro, Esteban Cvitkovic, Francesco Bertoni, Giorgio Inghirami
Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27792904/epstein-barr-virus-latent-membrane-protein-2a-lmp2a-enhances-il-10-production-through-the-activation-of-bruton-s-tyrosine-kinase-and-stat3
#18
Ryan Incrocci, Levi Barse, Amanda Stone, Sai Vagvala, Michael Montesano, Vijay Subramaniam, Michelle Swanson-Mungerson
Previous data demonstrate that Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 to promote the survival of LMP2A-expressing B cell lymphomas. Since STAT3 is an important regulator of IL-10 production, we hypothesized that LMP2A activates a signal transduction cascade that increases STAT3 phosphorylation to enhance IL-10. Using LMP2A-negative and -positive B cell lines, the data indicate that LMP2A requires the early signaling molecules of the Syk/RAS/PI3K pathway to increase IL-10. Additional studies indicate that the PI3K-regulated kinase, BTK, is responsible for phosphorylating STAT3, which ultimately mediates the LMP2A-dependent increase in IL-10...
January 2017: Virology
https://www.readbyqxmd.com/read/27784188/extended-follow-up-with-the-bruton-s-tyrosine-kinase-inhibitor-ibrutinib-in-previously-treated-waldenstr%C3%A3-m-s-macroglobulinemia
#19
Richard R Furman, Ying Luan, Elizabeth Bilotti, Thorsten Graef
No abstract text is available yet for this article.
October 26, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27776353/bruton-tyrosine-kinase-inhibitor-ono-gs-4059-from-bench-to-bedside
#20
Jingjing Wu, Mingzhi Zhang, Delong Liu
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been approved for the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. Acquired resistance to ibrutinib due to BTK C481S mutation has been reported. Mutations in PLCγ2 can also mediate resistance to ibrutinib. Untoward effects due to off-target effects are also disadvantages of ibrutinib. More selective and potent BTK inhibitors (ACP-196, ONO/GS-4059, BGB-3111, CC-292) are being investigated. This review summarized the preclinical research and clinical data of ONO/GS-4059...
October 20, 2016: Oncotarget
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