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https://www.readbyqxmd.com/read/29146136/identification-of-highly-potent-btk-and-jak3-dual-inhibitors-with-improved-activity-for-the-treatment-of-b-cell-lymphoma
#1
Yang Ge, Changyuan Wang, Shijie Song, Jiaxin Huang, Zhihao Liu, Yongming Li, Qiang Meng, Jianbin Zhang, Jihong Yao, Kexin Liu, Xiaodong Ma, Xiuli Sun
The BTK and JAK3 receptor tyrosine kinases are two validated and therapeutically amenable targets in the treatment of B-cell lymphomas. Here we report the identification of several classes of pyrimidine derivatives as potent BTK and JAK3 dual inhibitors. Among these molecules, approximately two thirds displayed strong inhibitory capacity at less than 10 nM concentration, and four compounds (7e, 7g, 7m and 7n) could significantly inhibit the phosphorylation of BTK and JAK3 enzymes at concentrations lower than 1 nM...
November 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29144032/microrna-106b-overexpression-alleviates-inflammation-injury-of-cardiac-endothelial-cells-by-targeting-blnk-via-the-nf-%C3%AE%C2%BAb-signaling-pathway
#2
Zhe An, Guang Yang, Wei Nie, Jin Ren, Dan Wang
We aim to investigate whether microRNA-106b (miR-106b) affects the inflammation injury of cardiac endothelial cells (ECs) by targeting B-cell linker (BLNK) via the NF-κB signaling pathway. Human cardiac microvascular endothelial cells (HCMECs) were assigned into the control, hypoxia/reoxygenation (H/R), negative control (NC), pyrrolidine dithiocarbamate (PDTC), miR-106b mimic, miR-106b inhibitor, and si-BLNK and miR-106b inhibitor + si-BLNK groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were conducted for miR-106b expression and expressions of BLNK, interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, NF-κB, pIκBα, BTK, and PLC-γ2...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29130484/the-bruton-s-tyrosine-kinase-inhibitor-prn473-inhibits-neutrophil-recruitment-via-inhibition-of-mac-1-signaling
#3
Jan M Herter, Andreas Margraf, Stephanie Volmering, Benedito Eduardo Correia, J Michael Bradshaw, Angelina Bisconte, Ronald J Hill, Claire L Langrish, Clifford A Lowell, Alexander Zarbock
BACKGROUND AND PURPOSE: Following inflammatory stimuli neutrophils are recruited to sites of inflammation and exert effector functions that often have deleterious effects on tissue integrity, which can lead to organ failure. Btk is expressed in neutrophils, and constitutes a promising pharmacological target for neutrophil mediated tissue damage. Here we evaluate a selective reversible inhibitor of the Bruton's tyrosine kinase (PRN473) for its ability to dampen neutrophil influx via inhibition of adhesion receptor signaling pathways...
November 11, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29129717/a-chemoproteomic-approach-to-query-the-degradable-kinome-using-a-multi-kinase-degrader
#4
Hai-Tsang Huang, Dennis Dobrovolsky, Joshiawa Paulk, Guang Yang, Ellen L Weisberg, Zainab M Doctor, Dennis L Buckley, Joong-Heui Cho, Eunhwa Ko, Jaebong Jang, Kun Shi, Hwan Geun Choi, James D Griffin, Ying Li, Steven P Treon, Eric S Fischer, James E Bradner, Li Tan, Nathanael S Gray
Heterobifunctional molecules that recruit E3 ubiquitin ligases, such as cereblon, for targeted protein degradation represent an emerging pharmacological strategy. A major unanswered question is how generally applicable this strategy is to all protein targets. In this study, we designed a multi-kinase degrader by conjugating a highly promiscuous kinase inhibitor with a cereblon-binding ligand, and used quantitative proteomics to discover 28 kinases, including BTK, PTK2, PTK2B, FLT3, AURKA, AURKB, TEC, ULK1, ITK, and nine members of the CDK family, as degradable...
November 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29127086/mainstreaming-cryo-em-in-cancer-research
#5
(no author information available yet)
Cryo-electron microscopy, whose pioneers won the 2017 Nobel Prize in Chemistry, is gaining favor among scientists as a tool to probe cancer at the molecular level. To that end, the NCI recently launched a centralized, free service facility to better meet the needs of researchers interested in utilizing this otherwise highly expensive technology.
November 10, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29125406/bruton-s-tyrosine-kinase-inhibitors-first-and-second-generation-agents-for-patients-with-chronic-lymphocytic-leukemia-cll
#6
Philip A Thompson, Jan A Burger
The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy...
November 10, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29122993/the-microenvironmental-stromal-cells-abrogate-nf-%C3%AE%C2%BAb-inhibitor-induced-apoptosis-in-chronic-lymphocytic-leukemia
#7
Carl Philipp Simon-Gabriel, Katharina Foerster, Shifa Saleem, Dorothee Bleckmann, Marco Benkisser-Petersen, Nicolas Thornton, Kazuo Umezawa, Sarah Decker, Meike Burger, Hendrik Veelken, Rainer Claus, Christine Dierks, Justus Duyster, Katja Zirlik
NF-κB is known to play an important role in the pathogenesis of chronic lymphocytic leukemia. Several NF-κB inhibitors have been shown to successfully induce apoptosis of chronic lymphocytic leukemia cells in vitro. Since the microenvironment is known to be crucial for the survival of chronic lymphocytic leukemia cells, we tested here whether NF-κB inhibition may still induce apoptosis in these leukemic cells in the presence of protective stromal interaction. We used the specific NF-κB inhibitor Dehydroxymethylepoxyquinomicin...
November 9, 2017: Haematologica
https://www.readbyqxmd.com/read/29115892/management-of-patients-with-chronic-lymphocytic-leukemia-at-high-risk-of-relapse-on-ibrutinib-therapy
#8
Ayed O Ayed, Sameer A Parikh
The past two decades have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL), particularly with the introduction of targeted therapies to clinical practice. Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and has shown significant efficacy and tolerability, even in heavily treated patients. Despite improvement in outcomes, patients do ultimately relapse. Those who develop disease progression on ibrutinib are a particularly high-risk population with poor outcomes...
November 8, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29108275/functional-imaging-in-combination-with-mutation-status-aids-prediction-of-response-to-inhibiting-b-cell-receptor-signaling-in-lymphoma
#9
Laura Jacobs, Stefan Habringer, Jolanta Slawska, Katharina Huber, Elke Hauf, Zhoulei Li, Yosef Refaeli, Markus Schwaiger, Martina Rudelius, Axel Walch, Ulrich Keller
Aberrant B-cell receptor (BCR) signaling is known to contribute to malignant transformation. Two small molecule inhibitors targeting BCR pathway signaling include ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, and idelalisib, a specific Phosphatidylinositol-4,5-bisphosphate 3-kinase delta (PI3Kδ) inhibitor, both of which have been approved for use in haematological malignancies. Despite the identification of various diffuse large B-cell lymphoma (DLBCL) subtypes, mutation status alone is not sufficient to predict patient response and therapeutic resistance can arise...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29082795/treatment-approach-for-elderly-and-unfit-patients-with-chronic-lymphocytic-leukemia
#10
Idanna Innocenti, Francesco Autore, Raffaella Pasquale, Francesca Morelli, Dimitar G Efremov, Luca Laurenti
Elderly patients with chronic lymphocytic leukemia (CLL) or patients with comorbidities are often treated with chlorambucil (Chl) as front-line therapy despite relatively low response rates. The addition of a monoclonal anti-CD20 antibody to Chl substantially increases response rates and prolongs progression-free survival (PFS) in these patients, without increasing toxicity. As a result, the ESMO guidelines recommend that previously untreated CLL patients with relevant co-morbidity, but without TP53 deletion/mutation, should be treated with the combination of Chl plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab)...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29074501/single-agent-ibrutinib-in-relapsed-or-refractory-follicular-lymphoma-a-phase-2-consortium-trial
#11
Nancy L Bartlett, Brian A Costello, Betsy R LaPlant, Stephen M Ansell, John G Kuruvilla, Craig B Reeder, Lim S Thye, Daniel M Anderson, Kilannin Krysiak, Cody Ramirez, Jing Qi, Barry A Siegel, Malachi Griffith, Obi L Griffith, Felicia Gomez, Todd A Fehniger
Most patients with follicular lymphoma experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in follicular lymphoma in a Phase 1 study. We report the results of a Phase 2 trial evaluating ibrutinib in recurrent follicular lymphoma. Forty patients with recurrent follicular lymphoma were treated with ibrutinib, 560 mg/day until progression or intolerance. The primary endpoint was overall response rate...
October 26, 2017: Blood
https://www.readbyqxmd.com/read/29070143/-differential-regulation-of-bruton-s-tyrosine-kinase-by-the-ubiquitin-pathway
#12
Yi-Jia Fang, Yuan-Yuan Hu, Lan-Lan Ling, Yue Chen, Yu-Ye Shi, Li Zhang, Chun-Ling Wang, Liang Yu
OBJECTIVE: To investigate the regulation of Bruton's tyrosine kinase (Btk) and to explore its possible mechanism. METHODS: After treatment with the proteasome inhibitors and/or phorbol esters (PMA), the mRNA and protein expression level of Btk was detected by RT-PCR and Western blot, respectively. The ubiquitination level of Btk in B lymphoblastoid A20 cells was estimated after stimulation via the crosslinking of BCR with anti-IgM antibody. The cotransfection of COS-7 cell with Btk, ubiquitin and Cbl was performed, then the ubiquitination level of Btk was measured...
October 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29069762/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#13
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5(+) B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5(+)CD43(+)IgM(+)CD19(+) CLL phenotype in culture and can be adoptively transferred into Rag1(-/-) mice...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29061802/myd88-inhibitor-st2825-suppresses-the-growth-of-lymphoma-and-leukaemia-cells
#14
Erika Shiratori, Mai Itoh, Shuji Tohda
BACKGROUND/AIM: Myeloid differentiation primary response gene 88 (MYD88), which activates the nuclear factor kappa B (NF-κB) pathway, is important for the growth of lymphoma and leukaemia cells. In this study, we investigated the effects of ST2825, a synthetic peptidomimetic compound which inhibits MYD88 homodimerization, on their growth. MATERIALS AND METHODS: Seven lymphoma and leukaemia cell lines including TMD8, a B-cell lymphoma line with MYD88-activating mutation, were treated with ST2825 and analysed for cell proliferation and expression of NF-κB signalling-related molecules...
November 2017: Anticancer Research
https://www.readbyqxmd.com/read/28993409/malt1-inhibition-is-efficacious-in-both-na%C3%A3-ve-and-ibrutinib-resistant-chronic-lymphocytic-leukemia
#15
Nakhle S Saba, Deanna H Wong, Georges Tanios, Jessica R Iyer, Patricia Lobelle-Rich, Eman L Dadashian, Delong Liu, Lorena Fontan, Erik K Flemington, Cydney M Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E M Herman
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma...
October 9, 2017: Cancer Research
https://www.readbyqxmd.com/read/28972595/ibrutinib-modulates-the-immunosuppressive-cll-microenvironment-through-stat3-mediated-suppression-of-regulatory-b-cell-function-and-inhibition-of-the-pd-1-pd-l1-pathway
#16
K Kondo, H Shaim, P A Thompson, J A Burger, M Keating, Z Estrov, D Harris, E Kim, A Ferrajoli, M Daher, R Basar, M Muftuoglu, N Imahashi, A Alsuliman, C Sobieski, E Gokdemir, W Wierda, N Jain, E Liu, E J Shpall, K Rezvani
Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies...
October 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28958786/-lymphomas-a-therapeutic-update
#17
REVIEW
A Wolfromm, R Delarue
Emergence of new molecules has considerably reshaped the management of patients in onco-hematology. Cytotoxic chemotherapy has not been altered, and CHOP remains the reference treatment for lymphomas. However, the development of targeted therapies has allowed for a broader spectrum of treatments. Immunotherapy with monoclonal antibodies entered the market with rituximab in diffuse large B-cell lymphomas, in the 1990s and it is now developing as new-generation anti-CD20 antibodies (obinotuzumab and ofatumumab)...
October 2017: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/28950886/hm71224-a-selective-bruton-s-tyrosine-kinase-inhibitor-attenuates-the-development-of-murine-lupus
#18
Yu-Yon Kim, Ki Tae Park, Sun Young Jang, Kyu Hang Lee, Joo-Yun Byun, Kwee Hyun Suh, Young-Mi Lee, Young Hoon Kim, Kwang Woo Hwang
BACKGROUND: Systemic lupus erythematosus (SLE) is associated with B cell hyperactivity, and lupus nephritis (LN), in particular, is promoted by the production of autoantibodies and immune complex deposition. Bruton's tyrosine kinase (BTK) plays critical roles in B cell receptor-related and Fc receptor-related signaling. We aimed to investigate the impact of therapeutic intervention with HM71224 (LY3337641), a selective BTK inhibitor, on the development of murine SLE-like disease features...
September 26, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28946903/high-expression-of-bruton-s-tyrosine-kinase-btk-is-required-for-egfr-induced-nf-%C3%AE%C2%BAb-activation-and-predicts-poor-prognosis-in-human-glioma
#19
Chenglong Yue, Mingshan Niu, Qian Qian Shan, Ting Zhou, Yiming Tu, Peng Xie, Lei Hua, Rutong Yu, Xuejiao Liu
BACKGROUND: Malignant glioma is the most common primary brain tumor in adults and has a poor prognosis. However, there are no effective targeted therapies for glioma patients. Thus, the development of novel targeted therapeutics for glioma is urgently needed. METHODS: In this study, we examined the prognostic significance BTK expression in patients with glioma. Furthermore, we investigated the mechanism and therapeutic potential of ibrutinib in the treatment of human glioma in vitro and in vivo...
September 25, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28945083/in-silico-identification-of-a-novel-hinge-binding-scaffold-for-kinase-inhibitor-discovery
#20
Yanli Wang, Yuze Sun, Ran Cao, Dan Liu, Yuting Xie, Li Li, Xiangbing Qi, Niu Huang
To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers...
October 16, 2017: Journal of Medicinal Chemistry
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