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Bruton tyrosine kinase

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https://www.readbyqxmd.com/read/29457982/discovery-of-gdc-0853-a-potent-selective-and-non-covalent-bruton-s-tyrosine-kinase-inhibitor-in-early-clinical-development
#1
James J Crawford, Adam R Johnson, Dinah L Misner, Lisa D Belmont, Georgette M Castanedo, Regina Choy, Melis Coraggio, Liming Dong, Charles Eigenbrot, Rebecca Erickson, Nico Ghilardi, Jonathan Hau, Arna Katewa, Pawan Bir Kohli, Wendy Lee, Joseph W Lubach, Brent S McKenzie, Daniel Fred Ortwine, Leah Schutt, Suzanne Tay, Binqing Wei, Karin Reif, Lichuan Liu, Harvey Wong, Wendy B Young
Btk is a non-receptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Pre-clinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and pre-clinical characterization of a potent, selective, and non-covalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease, and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis...
February 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29455639/role-of-bruton-s-tyrosine-kinase-in-b-cells-and-malignancies
#2
REVIEW
Simar Pal Singh, Floris Dammeijer, Rudi W Hendriks
Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR). More recently, small-molecule inhibitors of this kinase have shown excellent anti-tumor activity, first in animal models and subsequently in clinical studies...
February 19, 2018: Molecular Cancer
https://www.readbyqxmd.com/read/29454849/escmid-study-group-for-infections-in-compromised-hosts-esgich-consensus-document-on-the-safety-of-targeted-and-biological-therapies-an-infectious-diseases-perspective-intracellular-signaling-pathways-tyrosine-kinase-and-mtor-inhibitors
#3
REVIEW
Mark Reinwald, Jose T Silva, Nicolas J Mueller, Jesús Fortún, Christian Garzoni, Johan W de Fijter, Mario Fernández-Ruiz, Paolo Grossi, Jose María Aguado
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family...
February 15, 2018: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29452660/novel-therapies-for-relapsed-refractory-mantle-cell-lymphoma
#4
REVIEW
Puja C Arora, Craig A Portell
Mantle cell lymphoma is an aggressive Non-Hodgkin's lymphoma that is considered incurable with standard therapies. Most patients treated with frontline immunochemotherapy relapse within a few years and do not usually respond to salvage chemotherapy. Persistent activation of the B-cell receptor pathway is critical to the pathogenesis of mantle cell lymphoma. Inhibition of Bruton's tyrosine kinase, an essential B-cell receptor pathway component with ibrutinib has shown clinical activity and has changed how MCL is treated in the relapsed/refractory setting...
March 2018: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29441438/combining-ibrutinib-with-chk1-inhibitors-synergistically-targets-mantle-cell-lymphoma-cell-lines
#5
Valentina Restelli, Monica Lupi, Micaela Vagni, Rosaria Chilà, Francesco Bertoni, Giovanna Damia, Laura Carrassa
BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton's tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment...
February 13, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29435979/ibrutinib-alone-or-with-dexamethasone-for-relapsed-or-relapsed-and-refractory-multiple-myeloma-phase-2-trial-results
#6
Paul G Richardson, William I Bensinger, Carol Ann Huff, Caitlin L Costello, Nikoletta Lendvai, Jesus G Berdeja, Larry D Anderson, David S Siegel, Daniel Lebovic, Sundar Jagannath, Jacob P Laubach, Keith E Stockerl-Goldstein, Long Kwei, Fong Clow, Laurence Elias, Zeena Salman, Thorsten Graef, Elizabeth Bilotti, Ravi Vij
Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low-dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2-stage design...
February 13, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29424919/ibrutinib-presents-antitumor-activity-in-skin-cancer-and-induces-autophagy
#7
F-D Sun, P-C Wang, J Shang, S-H Zou, X Du
OBJECTIVE: Skin cancer is one of the most common malignancies in dermatology. Patient compliance and prognosis of skin cancer are poor. Ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor, is a new anticancer drug used to treat many cancers. Therefore, we aimed to explore the role of ibrutinib in the treatment of skin cancer. MATERIALS AND METHODS: Cell Counting Kit-8 (CCK8) and plate cloning assay were used to detect cell proliferation. Apoptosis was determined by flow cytometry...
January 2018: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29401630/tetrandrine-attenuates-the-bone-erosion-in-collagen-induced-arthritis-rats-by-inhibiting-osteoclastogenesis-via-spleen-tyrosine-kinase
#8
Yugai Jia, Yumeng Miao, Mengfan Yue, Mei Shu, Zhifeng Wei, Yue Dai
Tetrandrine, a bisbenzylisoquinoline alkaloid, was previously demonstrated to attenuate inflammation and cartilage destruction in the ankles of mice with collagen-induced arthritis (CIA). Here, we explored the underlying mechanism by which tetrandrine prevented arthritis-induced bone erosion by focusing on the differentiation and function of osteoclasts. We found that daily administration of tetrandrine (30 mg/kg) markedly reduced the bone damage and decreased the number of osteoclasts in CIA rats. In vitro, tetrandrine inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis at the early stage and reduced the expressions of osteoclast-related marker genes...
January 30, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29391515/heterologous-pathway-assembly-reveals-molecular-steps-of-fungal-terreic-acid-biosynthesis
#9
Chuixing Kong, Hezhou Huang, Ying Xue, Yiqi Liu, Qiangqiang Peng, Qi Liu, Qin Xu, Qiaoyun Zhu, Ying Yin, Xiangshan Zhou, Yuanxing Zhang, Menghao Cai
Terreic acid is a potential anticancer drug as it inhibits Bruton's tyrosine kinase; however, its biosynthetic molecular steps remain unclear. In this work, the individual reactions of terreic acid biosynthesis were determined by stepwise pathway assembly in a heterologous host, Pichia pastoris, on the basis of previous knockout studies in a native host, Aspergillus terreus. Polyketide synthase AtX was found to catalyze the formation of partially reduced polyketide 6-methylsalicylic acid, followed by 3-methylcatechol synthesis by salicylate 1-monooxygenase AtA-mediated decarboxylative hydroxylation of 6-methylsalicylic acid...
February 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29386196/a-phase-i-study-of-ibrutinib-in-combination-with-r-ice-in-patients-with-relapsed-or-primary-refractory-dlbcl
#10
Craig S Sauter, Matthew J Matasar, Heiko Schoder, Sean M Devlin, Pamela Drullinsky, John Gerecitano, Anita Kumar, Ariela Noy, Maria L Palomba, Carol S Portlock, David J Straus, Andrew D Zelenetz, Susan J McCall, Shoshana T Miller, Amanda I Courtien, Anas Younes, Craig H Moskowitz
In the post-rituximab era, approximately half the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation (ASCT) with curative intent. The Bruton's tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell-of-origin (COO). We conducted a single center phase I study evaluating dose escalated ibrutinib, in a 3 by 3 design, in combination with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients...
January 31, 2018: Blood
https://www.readbyqxmd.com/read/29383704/platelets-at-the-crossroads-of-thrombosis-inflammation-and-haemolysis
#11
Sebastian Vogel, Swee Lay Thein
Platelets play a critical role at the interphase of thrombosis and inflammation, key features in haemolysis-associated disorders. Exercising this role requires expression of pattern recognition receptors by platelets, including toll-like receptor 4 (TLR4) and nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3), the latter forming intraplatelet multiprotein inflammasome complexes. Platelets are a potential target of various damage-associated molecular pattern (DAMP) molecules, such as free haem, a degradation by-product of haemoglobin oxidation during haemolysis, and high-mobility group box 1 (HMGB1), a DNA-binding protein released by dying or stressed cells and activated platelets...
January 30, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29370834/highly-selective-inhibition-of-bruton-s-tyrosine-kinase-attenuates-skin-and-brain-disease-in-murine-lupus
#12
Samantha A Chalmers, Jing Wen, Jessica Doerner, Ariel Stock, Carla M Cuda, Hadijat M Makinde, Harris Perlman, Todd Bosanac, Deborah Webb, Gerald Nabozny, Jay S Fine, Elliott Klein, Meera Ramanujam, Chaim Putterman
BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. METHODS: We used a novel inhibitor of Bruton's tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease...
January 25, 2018: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29364178/disrupting-the-btk-pathway-suppresses-copd-like-lung-alterations-in-atherosclerosis-prone-apoe-mice-following-regular-exposure-to-cigarette-smoke
#13
Jon M Florence, Agnieszka Krupa, Laela M Booshehri, Adrian L Gajewski, Anna K Kurdowska
Chronic obstructive pulmonary disease (COPD) is associated with severe chronic inflammation that promotes irreversible tissue destruction. Moreover, the most broadly accepted cause of COPD is exposure to cigarette smoke. There is no effective cure and significantly, the mechanism behind the development and progression of this disease remains unknown. Our laboratory has demonstrated that Bruton's tyrosine kinase (Btk) is a critical regulator of pro-inflammatory processes in the lungs and that Btk controls expression of matrix metalloproteinase-9 (MMP-9) in the alveolar compartment...
January 24, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29359797/ibrutinib-resistance-in-mantle-cell-lymphoma-clinical-molecular-and-treatment-aspects
#14
REVIEW
Oshrat Hershkovitz-Rokah, Dana Pulver, Georg Lenz, Ofer Shpilberg
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder comprising about 6-10% of all B cell lymphoma cases. Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. Although treatment with ibrutinib has significantly improved the outcome of MCL patients, approximately one-third of the patients have primary drug resistance while others appear to develop acquired resistance. Understanding the molecular events leading to the primary and acquired resistance to ibrutinib is essential for achieving better outcomes in patients with MCL...
January 23, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29348675/stac2-negatively-regulates-osteoclast-formation-by-targeting-the-rank-signaling-complex
#15
Eutteum Jeong, Han Kyoung Choi, Jin Hee Park, Soo Young Lee
The receptor activator of nuclear factor-κB (RANK) protein activates various protein kinase signaling cascades, including those involving NF-κB, mitogen-activated protein kinase (MAPK), and Bruton tyrosine kinase (Btk)/tyrosine-protein kinase Tec. However, the mechanism underlying the negative regulation of RANK by downstream signaling molecules remains unclear. Here, we report that Src homology 3 domain and cysteine-rich domain-containing protein 2 (STAC2) is a novel RANK ligand-inducible protein that negatively regulates RANK-mediated osteoclast formation...
January 18, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29348577/targeting-b-cell-receptor-signalling-in-cancer-preclinical-and-clinical-advances
#16
REVIEW
Jan A Burger, Adrian Wiestner
B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling...
January 19, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29347836/strategies-to-overcome-resistance-mutations-of-bruton-s-tyrosine-kinase-inhibitor-ibrutinib
#17
Linyi Liu, Bingyu Shi, Xiangqian Wang, Hua Xiang
Ibrutinib, as the first Bruton's tyrosine kinase (Btk) inhibitor, has been shown to have clinically significant activity in leukemias and lymphomas. However, the initially responsive tumors will develop resistance during the process of treatment in few patients. Here, we summarized the mechanism of acquired resistance and suggested the next-generation Btk inhibitors that override the target resistance. Moreover, the development of combination of selective antagonists or inhibitors targeting to multiple protein kinases have increased therapeutic potency to reduce the risk of the emergence of kinases inhibitor resistance...
January 19, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29333021/efficacy-and-safety-of-ibrutinib-in-indian-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia-and-mantle-cell-lymphoma-cases-from-a-named-patient-program
#18
Mohan B Agarwal, Dinesh Bhurani, Chirag Shah, Nitin Sood, Manish Singhal, Anil Kamat, Subash Chezhian, Suryaprakash Mishra, Dinesh Nagrale
Context: This named patient program evaluated the safety and efficacy of ibrutinib, a selective inhibitor of Bruton's tyrosine kinase in Indian patients with relapsed/refractory chronic lymphocytic leukemia (CLL, with/without chromosome 17 deletion [del17p]) and mantle cell lymphoma (MCL). Subjects and Methods: The eight enrolled patients (relapsed/refractory CLL: n = 6 [4/6 patients with del17p] and relapsed/refractory MCL: n = 2) had median age of 55 years (range, 52-60) and had received a median of 3 (CLL patients) and 4 (MCL patients) prior therapies...
October 2017: Indian Journal of Medical and Paediatric Oncology
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
#19
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/29320977/ibrutinib-targets-microrna-21-in-multiple-myeloma-cells-by-inhibiting-nf-%C3%AE%C2%BAb-and-stat3
#20
Jing Ma, Wei Gong, Su Liu, Qian Li, Mengzheng Guo, Jinhan Wang, Suying Wang, Naiyao Chen, Yafei Wang, Qiang Liu, Hui Zhao
The oncogenic microRNA-21 contributes to the pathogenesis of multiple myeloma. Ibrutinib (also referred to as PCI-32765), an inhibitor of Bruton's tyrosine kinase, while its effects on multiple myeloma have not been well described. Here, we show that microRNA-21 is an oncogenic marker closely linked with progression of multiple myeloma. Moreover, ibrutinib attenuates microRNA-21 expression in multiple myeloma cells by inhibiting nuclear factor-κB and signal transducer and activator of transcription 3 signaling pathways...
January 2018: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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