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Bruton tyrosine kinase

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
https://www.readbyqxmd.com/read/28378771/mediation-of-transitional-b-cell-maturation-in-the-absence-of-functional-bruton-s-tyrosine-kinase
#11
Shalini Tanwar, Atika Dhar, Vineeth Varanasi, Tapas Mukherjee, Ramanamurthy Boppana, Soumen Basak, Vineeta Bal, Anna George, Satyajit Rath
X-linked immune-deficient (Xid) mice, carrying a mutation in Bruton's tyrosine kinase (Btk), have multiple B cell lineage differentiation defects. We now show that, while Xid mice showed only mild reduction in the frequency of the late transitional (T2) stage of peripheral B cells, the defect became severe when the Xid genotype was combined with either a CD40-null, a TCRbeta-null or an MHC class II (MHCII)-null genotype. Purified Xid T1 and T2 B cells survived poorly in vitro compared to wild-type (WT) cells...
April 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28377877/invasive-aspergillosis-related-to-ibrutinib-therapy-for-chronic-lymphocytic-leukemia
#12
Benjamin Arthurs, Kathy Wunderle, Maylee Hsu, Suil Kim
We report a case of invasive pulmonary aspergillosis in a patient taking ibrutinib, a Bruton's tyrosine kinase inhibitor used to treat refractory chronic lymphocytic leukemia. We hypothesize that ibrutinib promoted this infection by suppressing innate immune responses against Aspergillus. Clinicians should be aware of potential Aspergillus infections in patients treated with this drug.
2017: Respiratory Medicine Case Reports
https://www.readbyqxmd.com/read/28377400/long-term-follow-up-of-patients-with-cll-treated-with-the-selective-bruton-s-tyrosine-kinase-inhibitor-ono-gs-4059
#13
Harriet S Walter, Sandrine Jayne, Simon A Rule, Guillaume Cartron, Franck Morschhauser, Salvador Macip, Lionel Karlin, Ceri Jones, Charles Herbaux, Philippe Quittet, Nimish Shah, Claire V Hutchinson, Christopher Fegan, Yingsi Yang, Siddhartha Mitra, Gilles Salles, Martin J S Dyer
No abstract text is available yet for this article.
April 4, 2017: Blood
https://www.readbyqxmd.com/read/28373262/impact-of-ibrutinib-dose-adherence-on-therapeutic-efficacy-in-patients-with-previously-treated-cll-sll
#14
Paul M Barr, Jennifer R Brown, Peter Hillmen, Susan O'Brien, Jacqueline C Barrientos, Nishitha M Reddy, Steven Coutre, Stephen P Mulligan, Ulrich Jaeger, Richard R Furman, Florence Cymbalista, Marco Montillo, Claire Dearden, Tadeusz Robak, Carol Moreno, John M Pagel, Jan A Burger, Samuel Suzuki, Juthamas Sukbuntherng, George Cole, Danelle F James, John C Byrd
Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with CLL that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE(TM) trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ~9 months. Pharmacokinetic assessment of ibrutinib exposure at 420 mg dose suggested similar exposure regardless of patient weight or age...
April 3, 2017: Blood
https://www.readbyqxmd.com/read/28369144/ankrd54-preferentially-selects-bruton-s-tyrosine-kinase-btk-from-a-human-src-homology-3-sh3-domain-library
#15
Manuela O Gustafsson, Dara K Mohammad, Erkko Ylösmäki, Hyunseok Choi, Subhash Shrestha, Qing Wang, Beston F Nore, Kalle Saksela, C I Edvard Smith
Bruton's Tyrosine Kinase (BTK) is a cytoplasmic protein tyrosine kinase with a fundamental role in B-lymphocyte development and activation. The nucleocytoplasmic shuttling of BTK is specifically modulated by the Ankyrin Repeat Domain 54 (ANKRD54) protein and the interaction is known to be exclusively SH3-dependent. To identify the spectrum of the ANKRD54 SH3-interactome, we applied phage-display screening of a library containing all the 296 human SH3 domains. The BTK-SH3 domain was the prime interactor. Quantitative western blotting analysis demonstrated the accuracy of the screening procedure...
2017: PloS One
https://www.readbyqxmd.com/read/28368423/myc-enhances-b-cell-receptor-signaling-in-precancerous-b-cells-and-confers-resistance-to-btk-inhibition
#16
T K Moyo, C S Wilson, D J Moore, C M Eischen
Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28366781/waldenstr%C3%A3-m-macroglobulinemia-review-of-pathogenesis-and-management
#17
REVIEW
Seongseok Yun, Ariel C Johnson, Onyemaechi N Okolo, Stacy J Arnold, Ali McBride, Ling Zhang, Rachid C Baz, Faiz Anwer
Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M. Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton tyrosine kinase inhibitors have made the management of WM increasingly complex...
March 7, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28361711/receptor-guided-3d-qsar-studies-molecular-dynamics-simulation-and-free-energy-calculations-of-btk-kinase-inhibitors
#18
Pavithra K Balasubramanian, Anand Balupuri, Hee-Young Kang, Seung Joo Cho
BACKGROUND: Bruton tyrosine kinase (Btk) plays an important role in B-cell development, differentiation, and signaling. It is also found be in involved in male immunodeficiency disease such as X-linked agammaglobulinemia (XLA). Btk is considered as a potential therapeutic target for treating autoimmune diseases and hematological malignancies. RESULTS: In this work, a combined molecular modeling study was performed on a series of thieno [3,2-c] pyridine-4-amine derivatives as Btk inhibitors...
March 14, 2017: BMC Systems Biology
https://www.readbyqxmd.com/read/28359287/activity-of-the-novel-bcr-kinase-inhibitor-iqs019-in-preclinical-models-of-b-cell-non-hodgkin-lymphoma
#19
P Balsas, A Esteve-Arenys, J Roldán, L Jiménez, V Rodríguez, J G Valero, A Chamorro-Jorganes, R Puig de la Bellacasa, J Teixidó, A Matas-Céspedes, A Moros, A Martínez, E Campo, A Sáez-Borderías, J I Borrell, P Pérez-Galán, D Colomer, G Roué
BACKGROUND: Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. METHODS: We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib...
March 31, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28353016/new-therapeutic-strategies-in-acute-lymphocytic-leukemia
#20
REVIEW
Louise M Man, Amy L Morris, Michael Keng
Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors...
March 28, 2017: Current Hematologic Malignancy Reports
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