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Btk inhibitor

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https://www.readbyqxmd.com/read/28915637/btk-suppresses-myeloma-cellular-senescence-through-activating-akt-p27-rb-signaling
#1
Chunyan Gu, Hailin Peng, Yue Lu, Hongbao Yang, Zhidan Tian, Gang Yin, Wen Zhang, Sicheng Lu, Yi Zhang, Ye Yang
We previously explored the role of BTK in maintaining multiple myeloma stem cells (MMSCs) self-renewal and drug-resistance. Here we investigated the elevation of BTK suppressing MM cellular senescence, a state of irreversible cellular growth arrest. We firstly discovered that an increased expression of BTK in MM samples compared to normal controls by immunohistochemistry (IHC), and significant chromosomal gain in primary samples. In addition, BTK high-expressing MM patients are associated with poor outcome in both Total Therapy 2 (TT2) and TT3 cohorts...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28905990/the-mtor-kinase-inhibitor-everolimus-synergistically-enhances-the-anti-tumor-effect-of-the-bruton-s-tyrosine-kinase-btk-inhibitor-pls-123-on-mantle-cell-lymphoma
#2
Jiao Li, Xiaogan Wang, Yan Xie, Zhitao Ying, Weiping Liu, Lingyan Ping, Chen Zhang, Zhengying Pan, Ning Ding, Yuqin Song, Jun Zhu
Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment...
September 14, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28901789/cardiac-side-effects-of-bruton-tyrosine-kinase-btk-inhibitors
#3
Chloe Pek Sang Tang, Julie McMullen, Constantine Tam
The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects...
September 13, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28882879/acalabrutinib-acp-196-a-covalent-bruton-tyrosine-kinase-btk-inhibitor-with-a-differentiated-selectivity-and-in-vivo-potency-profile
#4
Tjeerd Barf, Todd Covey, Raquel Izumi, Bas van de Kar, Michael Gulrajani, Bart van Lith, Maaike van Hoek, Edwin de Zwart, Diana Mittag, Dennis Demont, Saskia Verkaik, Fanny Krantz, Paul G Pearson, Roger Ulrich, Allard Kaptein
Several small-molecule BTK inhibitors are in development for B-cell malignancies and autoimmune disorders, each characterized by distinct potency and selectivity patterns. Herein we describe the pharmacologic characterization of BTK inhibitor acalabrutinib (1, ACP-196). Acalabrutinib possesses a reactive butynamide group that binds covalently to Cys481 in BTK. Relative to the other BTK inhibitors described here, the reduced intrinsic reactivity of acalabrutinib helps to limit inhibition of off-target kinases having cysteine-mediated covalent binding potential...
September 7, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28864770/retraction-abstract-408-acp-196-an-orally-bioavailable-covalent-selective-inhibitor-of-btk-modulates-the-innate-tumor-microenvironment-exhibits-antitumor-efficacy-and-enhances-gemcitabine-activity-in-pancreatic-cancer
#5
https://www.readbyqxmd.com/read/28838994/the-btk-inhibitor-cc-292-shows-activity-in-mantle-cell-lymphoma-and-synergizes-with-lenalidomide-and-nik-inhibitors-depending-on-the-nf-%C3%AE%C2%BAb-mutational-status
#6
Anna Vidal-Crespo, Vanina Rodriguez, Alba Matas-Céspedes, Eriong Lee, Alfredo Rivas-Delgado, Eva Giné, Alba Navarro, Sílvia Beà, Elías Campo, Armando López-Guillermo, Mónica López-Guerra, Gaël Roué, Dolors Colomer, Patricia Pérez-Galán
No abstract text is available yet for this article.
August 24, 2017: Haematologica
https://www.readbyqxmd.com/read/28830912/mapping-genetic-vulnerabilities-reveals-btk-as-a-novel-therapeutic-target-in-oesophageal-cancer
#7
Irene Yushing Chong, Lauren Aronson, Hanna Bryant, Aditi Gulati, James Campbell, Richard Elliott, Stephen Pettitt, Paul Wilkerson, Maryou B Lambros, Jorge S Reis-Filho, Anisha Ramessur, Michael Davidson, Ian Chau, David Cunningham, Alan Ashworth, Christopher J Lord
OBJECTIVE: Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited. DESIGN: To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations...
August 22, 2017: Gut
https://www.readbyqxmd.com/read/28792217/kinase-crystal-miner-a-powerful-approach-to-repurposing-3d-hinge-binding-fragments-and-its-application-to-finding-novel-bruton-tyrosine-kinase-inhibitors
#8
Prasenjit Mukherjee, Jörg Bentzien, Todd Bosanac, Wang Mao, Michael Burke, Ingo Muegge
Protein kinases represent an important target class for drug discovery because of their role in signaling pathways involved in disease areas such as oncology and immunology. A key element of many ATP-competitive kinase inhibitors is their hinge-binding motif. Here, we describe Kinase Crystal Miner (KCM)-a new approach developed at Boehringer Ingelheim (BI) that harvests the existing crystallographic information on kinase-inhibitor co-crystal structures from internal and external databases. About 1000 unique three-dimensional kinase inhibitor hinge binding motifs have been extracted from structures covering more than 180 different protein kinases...
August 28, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28791187/ibrutinib-treatment-of-mantle-cell-lymphoma-relapsing-at-central-nervous-system-a-case-report-and-literature-review
#9
Donato Mannina, Barbara Loteta
Mantle cell lymphoma (MCL) accounts for about 5% of all lymphomas. Its clinical and histological features are heterogeneous. After a frequently good initial response, the disease generally and repeatedly relapses and finally the outcome is poor. Particularly severe is the prognosis of the rare occurrence of CNSi (Central Nervous System involvement). Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has shown strong activity in relapsing patients with Chronic Lymphocytic Leukemia (CLL) and MCL. Few reports are available about treatment with ibrutinib of patients presenting CNSi by lymphoproliferative diseases (LPD)...
2017: Case Reports in Hematology
https://www.readbyqxmd.com/read/28760303/analysis-of-efficacy-and-tolerability-of-bruton-tyrosine-kinase-inhibitor-ibrutinib-in-various-b-cell-malignancies-in-the-general-community-a%C3%A2-single-center-experience
#10
Naveed Ali, Faizan Malik, Syed Imran Mustafa Jafri, Mary Naglak, Mark Sundermeyer, Peter V Pickens
BACKGROUND: Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), is a novel drug that has shown significant efficacy and survival benefit for treatment of various B-cell malignancies. The primary objective of the present study was to investigate the efficacy of ibrutinib therapy in various B-cell malignancies in the general community. The secondary objectives included studying the adverse effects, ibrutinib-induced peripheral lymphocytosis, and effect on immunoglobulin levels...
July 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28755313/targeting-b-cell-signaling-in-chronic-lymphocytic-leukemia
#11
REVIEW
Jon E Arnason, Jennifer R Brown
In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway...
September 2017: Current Oncology Reports
https://www.readbyqxmd.com/read/28751718/two-mouse-models-reveal-an-actionable-parp1-dependence-in-aggressive-chronic-lymphocytic-leukemia
#12
Gero Knittel, Tim Rehkämper, Darya Korovkina, Paul Liedgens, Christian Fritz, Alessandro Torgovnick, Yussor Al-Baldawi, Mona Al-Maarri, Yupeng Cun, Oleg Fedorchenko, Arina Riabinska, Filippo Beleggia, Phuong-Hien Nguyen, F Thomas Wunderlich, Monika Ortmann, Manuel Montesinos-Rongen, Eugen Tausch, Stephan Stilgenbauer, Lukas P Frenzel, Marco Herling, Carmen Herling, Jasmin Bahlo, Michael Hallek, Martin Peifer, Reinhard Buettner, Thorsten Persigehl, H Christian Reinhardt
Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge...
July 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28742141/bruton-s-tyrosine-kinase-inhibitor-bms-986142-in-experimental-models-of-rheumatoid-arthritis-enhances-efficacy-of-agents-representing-clinical-standard-of-care
#13
Kathleen M Gillooly, Claudine Pulicicchio, Mark A Pattoli, Lihong Cheng, Stacey Skala, Elizabeth M Heimrich, Kim W McIntyre, Tracy L Taylor, Daniel W Kukral, Shailesh Dudhgaonkar, Jignesh Nagar, Dana Banas, Scott H Watterson, Joseph A Tino, Aberra Fura, James R Burke
Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0...
2017: PloS One
https://www.readbyqxmd.com/read/28734581/discovery-of-r-5-benzo-d-1-3-dioxol-5-yl-7-1-vinylsulfonyl-pyrrolidin-2-yl-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-amine-b6-as-a-potent-bmx-inhibitor-for-the-treatment-of-nsclc
#14
Linhong He, Da Li, Chufeng Zhang, Peng Bai, Lijuan Chen
Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28720503/discovery-of-3-morpholino-imidazole-1-5-a-pyrazine-btk-inhibitors-for-rheumatoid-arthritis
#15
Sobhana Babu Boga, Abdul-Basit Alhassan, Jian Liu, Deodial Guiadeen, Arto Krikorian, Xiaolei Gao, James Wang, Younong Yu, Rajan Anand, Shilan Liu, Chundao Yang, Hao Wu, Jiaqiang Cai, Hugh Zhu, Jagdish Desai, Kevin Maloney, Ying-Duo Gao, Thierry O Fischmann, Jeremy Presland, My Mansueto, Zangwei Xu, Erica Leccese, Ian Knemeyer, Charles G Garlisi, Nathan Bays, Peter Stivers, Philip E Brandish, Alexandra Hicks, Alan Cooper, Ronald M Kim, Joseph A Kozlowski
8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28716053/ibrutinib-a-bruton-s-tyrosine-kinase-inhibitor-exhibits-antitumoral-activity-and-induces-autophagy-in-glioblastoma
#16
Jin Wang, Xiaoyang Liu, Yongzhi Hong, Songtao Wang, Pin Chen, Aihua Gu, Xiaoyuan Guo, Peng Zhao
BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM. METHODS: Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry...
July 17, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28714866/ibrutinib-treatment-improves-t-cell-number-and-function-in-cll-patients
#17
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L Mundy, Amber Gordon, Amy M Lehman, Kami J Maddocks, Carolyn Cheney, Jeffrey A Jones, Joseph M Flynn, Leslie A Andritsos, Farrukh Awan, Joseph A Fraietta, Carl H June, Marcela V Maus, Jennifer A Woyach, Michael A Caligiuri, Amy J Johnson, Natarajan Muthusamy, John C Byrd
BACKGROUND: Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton's tyrosine kinase (BTK) and IL-2-inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS: Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28705083/pyrrolo-2-3-d-pyrimidines-active-as-btk-inhibitors
#18
Francesca Musumeci, Monica Sanna, Chiara Greco, Ilaria Giacchello, Anna Lucia Fallacara, Rosario Amato, Silvia Schenone
Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages. Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors...
July 13, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28699667/mantle-cell-lymphoma-2017-update-on-diagnosis-risk-stratification-and-clinical-management
#19
REVIEW
Julie M Vose
DISEASE OVERVIEW: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. DIAGNOSIS: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1...
August 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28686599/flux-balance-analysis-predicts-warburg-like-effects-of-mouse-hepatocyte-deficient-in-mir-122a
#20
Hua-Qing Wu, Mei-Ling Cheng, Jin-Mei Lai, Hsuan-Hui Wu, Meng-Chun Chen, Wen-Huan Liu, Wu-Hsiung Wu, Peter Mu-Hsin Chang, Chi-Ying F Huang, Ann-Ping Tsou, Ming-Shi Shiao, Feng-Sheng Wang
The liver is a vital organ involving in various major metabolic functions in human body. MicroRNA-122 (miR-122) plays an important role in the regulation of liver metabolism, but its intrinsic physiological functions require further clarification. This study integrated the genome-scale metabolic model of hepatocytes and mouse experimental data with germline deletion of Mir122a (Mir122a-/-) to infer Warburg-like effects. Elevated expression of MiR-122a target genes in Mir122a-/-mice, especially those encoding for metabolic enzymes, was applied to analyze the flux distributions of the genome-scale metabolic model in normal and deficient states...
July 2017: PLoS Computational Biology
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