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https://www.readbyqxmd.com/read/29340061/analysis-of-the-mutational-landscape-of-classic-hodgkin-lymphoma-identifies-disease-heterogeneity-and-potential-therapeutic-targets
#1
Elena Mata, Antonio Díaz-López, Ana M Martín-Moreno, Margarita Sánchez-Beato, Ignacio Varela, María J Mestre, Carlos Santonja, Fernando Burgos, Javier Menárguez, Mónica Estévez, Mariano Provencio, Beatriz Sánchez-Espiridión, Eva Díaz, Carlos Montalbán, Miguel A Piris, Juan F García
Defining the mutational landscape of classic Hodgkin lymphoma is still a major research goal. New targeted next-generation sequencing (NGS) techniques may identify pathogenic mechanisms and new therapeutic opportunities related to this disease. We describe the mutational profile of a series of 57 cHL cases, enriched in Hodgkin and Reed-Sternberg (HRS) cells. Overall, the results confirm the presence of strong genomic heterogeneity. However, several variants were consistently detected in genes related to relevant signaling pathways, such as GM-CSF/IL-3, CBP/EP300, JAK/STAT, NF-kappaB, and numerous variants of genes affecting the B-cell receptor (BCR) pathway, such as BTK, CARD11, BCL10, among others...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29326436/p66shc-deficiency-enhances-cxcr4-and-ccr7-recycling-in-cll-b-cells-by-facilitating-their-dephosphorylation-dependent-release-from-%C3%AE-arrestin-at-early-endosomes
#2
Laura Patrussi, Nagaja Capitani, Francesca Cattaneo, Noemi Manganaro, Alessandra Gamberucci, Federica Frezzato, Veronica Martini, Andrea Visentin, Pier Giuseppe Pelicci, Mario M D'Elios, Livio Trentin, Gianpietro Semenzato, Cosima T Baldari
Neoplastic cell traffic abnormalities are central to the pathogenesis of chronic lymphocytic leukemia (CLL). Enhanced CXC chemokine receptor-4 (CXCR4) and chemokine receptor-7 (CCR7) recycling contributes to the elevated surface levels of these receptors on CLL cells. Here we have addressed the role of p66Shc, a member of the Shc family of protein adaptors the expression of which is defective in CLL cells, in CXCR4/CCR7 recycling. p66Shc reconstitution in CLL cells reduced CXCR4/CCR7 recycling, lowering their surface levels and attenuating B-cell chemotaxis, due to their accumulation in Rab5+ endosomes as serine-phosphoproteins bound to β-arrestin...
January 12, 2018: Oncogene
https://www.readbyqxmd.com/read/29324347/design-synthesis-and-biological-evaluation-of-7h-pyrrolo-2-3-d-pyrimidin-4-amine-derivatives-as-selective-btk-inhibitors-with-improved-pharmacokinetic-properties-for-the-treatment-of-rheumatoid-arthritis
#3
Linhong He, Heying Pei, Chufeng Zhang, Mingfeng Shao, Dan Li, Mingli Tang, Taijing Wang, Xiaoxin Chen, Mingli Xiang, Lijuan Chen
Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7H-pyrrolo [2,3-d]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro. Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16...
December 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29317997/experience-with-ibrutinib-for-first-line-use-in-patients-with-chronic-lymphocytic-leukemia
#4
REVIEW
Gilad Itchaki, Jennifer R Brown
Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations...
January 2018: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29301866/functional-and-clinical-relevance-of-vla-4-cd49d-cd29-in-ibrutinib-treated-chronic-lymphocytic-leukemia
#5
Erika Tissino, Dania Benedetti, Sarah E M Herman, Elisa Ten Hacken, Inhye E Ahn, Kari G Chaffee, Francesca Maria Rossi, Michele Dal Bo, Pietro Bulian, Riccardo Bomben, Elisabeth Bayer, Andrea Härzschel, Julia Christine Gutjahr, Massimiliano Postorino, Enrico Santinelli, Ayed Ayed, Francesco Zaja, Annalisa Chiarenza, Gabriele Pozzato, Alexandre Chigaev, Larry A Sklar, Jan A Burger, Alessandra Ferrajoli, Tait D Shanafelt, Adrian Wiestner, Giovanni Del Poeta, Tanja Nicole Hartmann, Valter Gattei, Antonella Zucchetto
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells...
January 4, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29296914/severe-platelet-dysfunction-in-nhl-patients-receiving-ibrutinib-is-absent-in-patients-receiving-acalabrutinib
#6
Alexander P Bye, Amanda J Unsworth, Michael J Desborough, Catherine A T Hildyard, Niamh Appleby, David Bruce, Neline Kriek, Sophie H Nock, Tanya Sage, Craig E Hughes, Jonathan M Gibbins
The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear...
December 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296874/crosstalk-between-ror1-and-bcr-pathways-defines-novel-treatment-strategies-in-mantle-cell-lymphoma
#7
Hanna Karvonen, David Chiron, Wilhelmiina Niininen, Sara Ek, Mats Jerkeman, Elaheh Moradi, Matti Nykter, Caroline A Heckman, Olli Kallioniemi, Astrid Murumägi, Daniela Ungureanu
Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin B-cell lymphoma with poor prognosis due to drug resistance. Introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib has markedly improved MCL therapy outcome, but drug resistance remains a challenge. The selective cell-surface expression of oncogenic receptor tyrosine kinase-like orphan receptor 1 (ROR1) pseudokinase in hematological malignancies has made this receptor a promising candidate for targeted therapy. We sought to identify the molecular mechanism underlying divergent ROR1-mediated apoptotic responses in MCL cell lines and primary samples...
November 14, 2017: Blood Advances
https://www.readbyqxmd.com/read/29285806/systematic-review-of-infectious-events-with-the-btk-inhibitor-ibrutinib-in-the-treatment-of-haematologic-malignancies
#8
REVIEW
Benjamin F Tillman, James M Pauff, Gowri Satyanarayana, Mahsa Talbott, Jeremy L Warner
OBJECTIVE: Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) in B-lymphocytes as well as other kinases including interleukin-2-inducible T-cell kinase (ITK) in CD4+ Th2 regulatory T-cells. Increased infections have been observed in patients taking ibrutinib. The overall incidence has not been systematically evaluated. METHODS: The published literature and conference abstracts of prospective clinical trials using ibrutinib in haematologic malignancies were identified and reviewed using PubMed, Google Scholar, and HemOnc...
December 28, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29276997/cancer-immunotherapy-in-a-neglected-population-the-current-use-and-future-of-t-cell-mediated-checkpoint-inhibitors-in-organ-transplant-patients
#9
REVIEW
Young Kwang Chae, Carlos Galvez, Jonathan F Anker, Wade T Iams, Manali Bhave
Although the indications for immune checkpoint inhibitors continue to grow, organ transplant recipients with advanced malignancies have been largely excluded from clinical trials testing the safety and efficacy of these therapies given their need for chronic immunosuppression and the risk of allograft rejection. With the rapid growth of transplant medicine and the increased risk of malignancy associated with chronic immunosuppression, it is critical that we systematically analyze the available data describing immune checkpoint blockade in the organ transplant population...
December 8, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29249817/drug-induced-inhibition-of-phosphorylation-of-stat5-overrides-drug-resistance-in-neoplastic-mast-cells
#10
B Peter, S Bibi, G Eisenwort, B Wingelhofer, D Berger, G Stefanzl, K Blatt, H Herrmann, E Hadzijusufovic, G Hoermann, T Hoffmann, J Schwaab, M Jawhar, M Willmann, W R Sperr, J Zuber, K Sotlar, H-P Horny, R Moriggl, A Reiter, M Arock, P Valent
Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29246942/synergistic-targeting-of-the-regulatory-and-catalytic-subunits-of-pi3k%C3%AE-in-mature-b-cell-malignancies
#11
Jeffrey Cooney, An-Ping Lin, Daifeng Jiang, Long Wang, Avvaru N Suhasini, Jamie Myers, ZhiJun Qiu, Albert Wölfler, Heinz Sill, Ricardo C T Aguiar
PURPOSE: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29246803/venetoclax-for-chronic-lymphocytic-leukaemia-progressing-after-ibrutinib-an-interim-analysis-of-a-multicentre-open-label-phase-2-trial
#12
Jeffrey A Jones, Anthony R Mato, William G Wierda, Matthew S Davids, Michael Choi, Bruce D Cheson, Richard R Furman, Nicole Lamanna, Paul M Barr, Lang Zhou, Brenda Chyla, Ahmed Hamed Salem, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, Steven Coutre, Jennifer Woyach, John C Byrd
BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy...
December 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29239533/corrigendum-discovery-of-a-potent-btk-inhibitor-with-a-novel-binding-mode-by-using-parallel-selections-with-a-dnaencoded-chemical-library
#13
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
No abstract text is available yet for this article.
December 14, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29208667/etk-interaction-with-pfkfb4-modulates-chemoresistance-of-small-cell-lung-cancer-by-regulating-autophagy
#14
Qiongyao Wang, Fanrui Zeng, Yanqin Sun, Qianqian Qiu, Jian Zhang, Weimei Huang, Jie Huang, Xiaomin Huang, Linlang Guo
PURPOSE: Epithelial and endothelial tyrosine kinase (Etk), also known as bone marrow X kinase (Bmx), was found to be critical in modulating the chemoresistance of small cell lung cancer (SCLC) in our preliminary study. However, the molecular mechanisms of Etk in SCLC chemoresistance remain poorly understood. The present study investigated the downstream factor and pathway involved. EXPERIMENTAL DESIGN: We demonstrated first that knockdown of Etk by siRNAs suppressed autophagy in chemoresistant SCLC cells, and that direct inhibition of autophagy sensitized cells to chemotherapy...
December 5, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29198867/design-and-synthesis-of-novel-pyrimidine-analogs-as-highly-selective-non-covalent-btk-inhibitors
#15
Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa
BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.
November 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29180734/btk-inhibitors-get-a-boost
#16
Asher Mullard
No abstract text is available yet for this article.
November 28, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29173980/-allogeneic-haematopoietic-cell-transplantation-for-diffuse-large-b-cell-lymphoma-guidelines-from-the-francophone-society-of-bone-marrow-transplantation-and-cellular-therapy-sfgm-tc
#17
Jordan Gauthier, Sylvain Chantepie, Krimo Bouabdallah, Edgar Jost, Stéphanie Nguyen, Anne-Claire Gac, Gandhi Damaj, Rémy Duléry, Mauricette Michallet, Jérémy Delage, Philippe Lewalle, Franck Morschhauser, Gilles Salles, Ibrahim Yakoub-Agha, Jérôme Cornillon
Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly in the case of after autologous stem cell transplantation if remission can be achieved. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma...
November 22, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29173978/-allogeneic-hematopoietic-cell-transplantation-for-hodgkin-s-disease-mantle-cell-lymphoma-and-other-rare-entities-guidelines-from-the-francophone-society-of-bone-marrow-transplantation-and-cellular-therapy-sfgm-tc
#18
Jordan Gauthier, Sylvain Chantepie, Krimo Bouabdallah, Edgar Jost, Stéphanie Nguyen, Anne-Claire Gac, Gandhi Damaj, Rémy Duléry, Mauricette Michallet, Jérémy Delage, Philippe Lewalle, Franck Morschhauser, Gilles Salles, Ibrahim Yakoub-Agha, Jérôme Cornillon
Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic haematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting...
November 22, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29173973/-allogeneic-haematopoietic-cell-transplantation-for-indolent-lymphomas-guidelines-from-the-francophone-society-bone-marrow-transplantation-and-cellular-therapy-sfgm-tc
#19
Jordan Gauthier, Sylvain Chantepie, Krimo Bouabdallah, Edgar Jost, Stéphanie Nguyen, Anne-Claire Gac, Gandhi Damaj, Rémy Duléry, Mauricette Michallet, Jérémy Delage, Philippe Lewalle, Franck Morschhauser, Gilles Salles, Ibrahim Yakoub-Agha, Jérôme Cornillon
Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting...
November 21, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29172502/discovery-and-optimisation-of-pyrrolopyrimidine-inhibitors-of-interleukin-1-receptor-associated-kinase-4-irak4-for-the-treatment-of-mutant-myd88l265p-diffuse-large-b-cell-lymphoma
#20
James S Scott, Sébastien L Degorce, Rana Anjum, Janet Culshaw, Robert M D Davies, Nichola L Davies, Keith S Dillman, James E Dowling, Lisa Drew, Andrew D Ferguson, Sam D Groombridge, Christopher T Halsall, Julian A Hudson, Scott Lamont, Nicola A Lindsay, Stacey K Marden, Michele F Mayo, J Elizabeth Pease, David R Perkins, Jennifer H Pink, Graeme R Robb, Alan Rosen, Minhui Shen, Claire McWhirter, Dedong Wu
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations...
November 27, 2017: Journal of Medicinal Chemistry
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