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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/28422989/the-lack-of-btk-does-not-impair-monocytes-and-polymorphonuclear-cells-functions-in-x-linked-agammaglobulinemia-under-treatment-with-intravenous-immunoglobulin-replacement
#4
Filomena Monica Cavaliere, Alessandro Prezzo, Caterina Bilotta, Metello Iacobini, Isabella Quinti
The lack of BTK in X-linked agammaglobulinemia (XLA) patients does not affect monocytes and polymorphonuclear cells (PMN) phenotype and functions. In this study, we show that XLA patients had an increased frequency of the intermediate monocytes subset and that BTK-deficient monocytes and PMN had a normal expression of receptors involved in the activation and cellular responses. We demonstrate that BTK is not required for migration, phagocytosis and the production of reactive oxygen species (ROS) following engagement of FC gamma receptors (FcγR)...
2017: PloS One
https://www.readbyqxmd.com/read/28419476/cortactin-a-lyn-substrate-is-a-checkpoint-molecule-at-the-intersection-of-bcr-and-cxcr4-signalling-pathway-in-chronic-lymphocytic-leukaemia-cells
#5
Veronica Martini, Cristina Gattazzo, Federica Frezzato, Valentina Trimarco, Marco Pizzi, Giorgia Chiodin, Filippo Severin, Edoardo Scomazzon, Vincenza Guzzardo, Deborah Saraggi, Flavia Raggi, Leonardo Martinello, Monica Facco, Andrea Visentin, Francesco Piazza, Anna Maria Brunati, Gianpietro Semenzato, Livio Trentin
Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28418267/btk-c481s-mediated-resistance-to-ibrutinib-in-chronic-lymphocytic-leukemia
#6
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/28407693/discovery-and-characterization-of-a-novel-irreversible-egfr-mutants-selective-and-potent-kinase-inhibitor-chmfl-egfr-26-with-a-distinct-binding-mode
#7
Chen Hu, Aoli Wang, Hong Wu, Ziping Qi, Xixiang Li, Xiao-E Yan, Cheng Chen, Kailin Yu, Fengming Zou, Wenchao Wang, Wei Wang, Jiaxin Wu, Juan Liu, Beilei Wang, Li Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Jing Liu, Qingsong Liu
EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type...
March 14, 2017: Oncotarget
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/28378609/antegrade-vs-crossover-femoral-artery-access-in-the-endovascular-treatment-of-isolated-below-the-knee-lesions-in-patients-with-critical-limb-ischemia
#12
Yukun Li, Ali Esmail, Konstantinos P Donas, Georgios Pitoulias, Giovanni Torsello, Theodosios Bisdas, Stefano Michelagnoli, Nicola Troisi
PURPOSE: To evaluate the safety and effectiveness of antegrade vs crossover femoral artery access in the endovascular treatment of isolated below-the-knee (BTK) lesions in patients with critical limb ischemia (CLI). METHODS: Between January 2014 and December 2015, 224 high-risk patients (mean age 75.8±9.8 years; 151 men) with CLI underwent infragenicular interventions on 292 crural vessels in 3 European vascular centers. All patients had isolated TransAtlantic Inter-Society Consensus (TASC) C (n=26) or D (n=198) BTK lesions...
April 1, 2017: Journal of Endovascular Therapy
https://www.readbyqxmd.com/read/28373262/impact-of-ibrutinib-dose-adherence-on-therapeutic-efficacy-in-patients-with-previously-treated-cll-sll
#13
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
#14
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/28369050/antagonism-of-b-cell-enhancer-networks-by-stat5-drives-leukemia-and-poor-patient-survival
#15
Casey D S Katerndahl, Lynn M Heltemes-Harris, Mark J L Willette, Christine M Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B Ramsey, Gregory Hubbard, Andrew D Wells, Roland P Kuiper, Blanca Scheijen, Frank N van Leeuwen, Markus Müschen, Steven M Kornblau, Michael A Farrar
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU...
April 3, 2017: Nature Immunology
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/28366935/plcg2-c2-domain-mutations-co-occur-with-btk-and-plcg2-resistance-mutations-in-chronic-lymphocytic-leukemia-undergoing-ibrutinib-treatment
#17
D Jones, J A Woyach, W Zhao, S Caruthers, H Tu, J Coleman, J C Byrd, A J Johnson, G Lozanski
Leukemia accepted article preview online, 03 April 2017. doi:10.1038/leu.2017.110.
April 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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/28359783/systematic-analysis-of-splicing-defects-in-selected-primary-immunodeficiencies-related-genes
#19
Lucie Grodecká, Pavla Hujová, Michal Kramárek, Tereza Kršjaková, Tatiana Kováčová, Katarína Vondrášková, Barbora Ravčuková, Kristýna Hrnčířová, Přemysl Souček, Tomáš Freiberger
Both variants affecting splice sites and those in splicing regulatory elements (SREs) can impair pre-mRNA splicing, eventually leading to severe diseases. Despite the availability of many prediction tools, prognosis of splicing affection is not trivial, especially when SREs are involved. Here, we present data on 92 in silico-/55 minigene-analysed variants detected in genes responsible for the primary immunodeficiencies development (namely BTK, CD40LG, IL2RG, SERPING1, STAT3, and WAS). Of 20 splicing-affecting variants, 16 affected splice site while 4 disrupted potential SRE...
March 27, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28359287/activity-of-the-novel-bcr-kinase-inhibitor-iqs019-in-preclinical-models-of-b-cell-non-hodgkin-lymphoma
#20
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
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