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https://www.readbyqxmd.com/read/27918558/quantitating-drug-target-engagement-in-single-cells-in-vitro-and-in-vivo
#1
J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt, Labros G Meimetis, Claudio Vinegoni, Ralph Weissleder
Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target...
December 5, 2016: Nature Chemical Biology
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/27899962/new-emerging-therapies-in-the-management-of-chronic-lymphocytic-leukemia
#7
Xiao-Lin Li, Ci-Xian Zhang
Chronic lymphocytic leukemia (CLL) is considered incurable despite advances in management strategies. New drugs targeting cell pathways are currently being developed for the efficient management of CLL. Various strategies involving different targets have been developed, or are currently in the developing stage. A search was conducted in the electronic database PubMed, for pre-clinical as well as clinically controlled trials reporting various strategies against CLL currently under investigation. Novel strategies included use of antibodies, small cell inhibitors, such as spleen tyrosine kinase, LYN, cyclin-dependent kinase, and histone deacetylase inhibitors...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27865897/enigmas-in-tumor-resistance-to-kinase-inhibitors-and-calculation-of-the-drug-resistance-index-for-cancer-dric
#8
REVIEW
C I Edvard Smith
Darwinian selection is also applicable when antibiotics, the immune system or other host factors shape the repertoire of microorganisms, and similarly, clonal selection is the hallmark of tumor evolution. The ongoing revolution in new anti-cancer treatment modalities, combined with an unprecedented precision in characterizing malignant clones at the level below one percent, profoundly improves the understanding of repertoire-tuning mechanisms. There is no fundamental difference between selection of the tumor cells in the presence, or absence, of therapy...
November 16, 2016: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/27825467/future-therapeutic-options-for-patients-with-waldenstr%C3%A3-m-macroglobulinemia
#9
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/27825466/current-therapy-guidelines-for-waldenstrom-s-macroglobulinaemia
#10
REVIEW
Efstathios Kastritis, Meletios A Dimopoulos
Waldenstrom's macroglobulinaemia (WM) is a B-cell neoplasm in which bone marrow is infiltrated by lymphoplasmacytic cells that secrete monoclonal immunoglobulin M (IgM). More than a decade ago, specific criteria were agreed to define diagnosis and symptomatic disease requiring therapy; however, treatment recommendations change as new options emerge. Treatment decisions consider specific disease characteristics (burden of disease, IgM levels, presence of cytopenias) and patient characteristics (age, comorbidities, toxicity)...
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/27825462/targeting-cell-adhesion-and-homing-as-strategy-to-cure-waldenstr%C3%A3-m-s-macroglobulinemia
#12
REVIEW
Steven T Pals, Marie José Kersten, Marcel Spaargaren
Most B-cell malignancies strictly depend on signals from the microenvironment for their survival and proliferation. This niche-dependency can be regarded as their Achilles' heel and provides an excellent target for therapy. Waldenström's macroglobulinemia (WM) is characterized by the accumulation of neoplastic post-germinal center B cells within the bone marrow (BM). Interestingly, one third of the patients carry activating mutations in the chemokine receptor CXCR4, a key mediator of B cell and plasma cell homing to the BM...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27821712/btk-small-molecule-inhibitors-induce-a-distinct-pancreatic-toxicity-in-rats
#13
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
#14
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/27813535/coinhibition-of-the-deubiquitinating-enzymes-usp14-and-uchl5-with-vlx1570-is-lethal-to-ibrutinib-or-bortezomib-resistant-waldenstrom-macroglobulinemia-tumor-cells
#15
A Paulus, S Akhtar, T R Caulfield, K Samuel, H Yousaf, Y Bashir, S M Paulus, D Tran, R Hudec, D Cogen, J Jiang, B Edenfield, A Novak, S M Ansell, T Witzig, P Martin, M Coleman, V Roy, S Ailawadhi, K Chitta, S Linder, A Chanan-Khan
The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics...
November 4, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27802969/ibrutinib-efficacy-and-tolerability-in-patients-with-relapsed-chronic-lymphocytic-leukemia-following-allogeneic-hct
#16
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/27799566/epigenetic-gene-regulation-by-janus-kinase-1-in-diffuse-large-b-cell-lymphoma
#17
Lixin Rui, Amanda C Drennan, Michele Ceribelli, Fen Zhu, George W Wright, Da Wei Huang, Wenming Xiao, Yangguang Li, Kreg M Grindle, Li Lu, Daniel J Hodson, Arthur L Shaffer, Hong Zhao, Weihong Xu, Yandan Yang, Louis M Staudt
Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
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
#18
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
#19
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
#20
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
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