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Btk inhibitor

Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Alessandro Gozzetti, Veronica Candi, Corrado Zuanelli Brambilla, Giulia Papini, Alberto Fabbri, Monica Bocchia
Abnormality of the B-cell receptor (BCR) signaling is correlated to origin of many B-cell malignancies.. Bruton's tyrosine kinase (BTK), is described as a possible target in a many B-cell neoplasms. Ibrutinib is the most used inhibitor of BTK and has great tolerability and efficacy in chronic lymphocytic leukemia. This review summarizes results with ibrutinib in clinical trials and novel BTK inhibitors of interest.
September 28, 2016: Anti-cancer Agents in Medicinal Chemistry
Prithviraj Bose, Varsha V Gandhi, Michael J Keating
Ibrutinib, a first-in-class covalent inhibitor of Bruton's tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease...
October 11, 2016: Expert Opinion on Drug Metabolism & Toxicology
Tomoko Yasuhiro, Wako Sawada, Christian Klein, Ryohei Kozaki, Shingo Hotta, Toshio Yoshizawa
The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates with poor prognosis. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101)...
August 9, 2016: Leukemia & Lymphoma
Jun Chen, Taisei Kinoshita, Juthamas Sukbuntherng, Betty Y Chang, Laurence Elias
Ibrutinib is a potent, small-molecule Bruton's tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nM); additionally the IC50s were lower than that of lapatinib and dacomitinib...
September 27, 2016: Molecular Cancer Therapeutics
(no author information available yet)
An article in the July 2016 issue, "Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma" by Gaurav Varma, MSPH, Tyler P. Johnson, MD, and Ranjana H. Advani, MD, described ONO/GS-4059 as a "reversible" inhibitor of BTK when it is in fact an "irreversible" inhibitor. We have made the correction to pages 546 and 552 of the online version at Many thanks to an astute reader for pointing out the error. This corrects the article pmid:27379948.
September 2016: Clinical Advances in Hematology & Oncology: H&O
Wafa A Mera, Malek Alzihlif, Mutasem O Taha, Mohammad A Khanfar
Bruton's Tyrosine Kinase (BTK) is a one of the Tec tyrosine kinase family. It has an essential role in B-cell development and function. Activation of BTK has been associated with the pathogenesis of many types of lymphomas and leukemia, and involved in non-life threatening autoimmune diseases. In this study, exhaustive pharmacophore modeling was combined with QSAR analyses to examine the structural requirements for anti-BTK activities. Genetic function algorithm (GFA) was coupled with multiple linear regression (MLR) analysis to select the best combinations of physicochemical descriptors and pharmacophoric hypothesis capable of generating predictive and self-consistent QSAR models...
September 26, 2016: Anti-cancer Agents in Medicinal Chemistry
C I E Smith
BTK is a cytoplasmic protein-tyrosine kinase, whose corresponding gene was isolated in the early 1990s. BTK was initially identified by positional cloning of the gene causing X-linked agammaglobulinemia and independently in a search for new kinases. Given the phenotype of affected patients, namely lack of B-lymphocytes and plasma cells with the ensuing inability to mount humoral immune responses, BTK inhibitors were anticipated to have beneficial effects on antibody-mediated pathologies, such as autoimmunity...
September 26, 2016: Oncogene
Mohammad Althubiti, Miran Rada, Jesvin Samuel, Josep M Escorsa, Hishyar Najeeb, Koon-Guan Lee, Kong-Peng Lam, George D D Jones, Nickolai A Barlev, Salvador Macip
p53 is a tumor suppressor that prevents the emergence of transformed cells by inducing apoptosis or senescence, among other responses. Its functions are regulated tightly by posttranslational modifications. Here we show that Bruton's tyrosine kinase (BTK) is a novel modulator of p53. We found that BTK is induced in response to DNA damage and p53 activation. BTK induction leads to p53 phosphorylation, which constitutes a positive feedback loop that increases p53 protein levels and enhances the transactivation of its target genes in response to stress...
September 15, 2016: Cancer Research
Shruti Sharma, Natalie Galanina, Ailin Guo, Jimmy Lee, Sabah Kadri, Charles Van Slambrouck, Bradley Long, Weige Wang, Mei Ming, Larissa V Furtado, Jeremy P Segal, Wendy Stock, Girish Venkataraman, Wei-Jen Tang, Pin Lu, Y Lynn Wang
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance...
September 10, 2016: Oncotarget
Aoli Wang, Xiao-E Yan, Hong Wu, Wenchao Wang, Chen Hu, Cheng Chen, Zheng Zhao, Peng Zhao, Xixiang Li, Li Wang, Beilei Wang, Zi Ye, Jinhua Wang, Chu Wang, Wei Zhang, Nathanael S Gray, Ellen L Weisberg, Liang Chen, Jing Liu, Cai-Hong Yun, Qingsong Liu
Ibrutinib, a clinically approved irreversible BTK kinase inhibitor for Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) etc, has been reported to be potent against EGFR mutant kinase and currently being evaluated in clinic for Non Small Cell Lung Cancer (NSCLC). Through EGFR wt/mutant engineered isogenic BaF3 cell lines we confirmed the irreversible binding mode of Ibrutinib with EGFR wt/mutant kinase via Cys797. However, comparing to typical irreversible EGFR inhibitor, such as WZ4002, the washing-out experiments revealed a much less efficient covalent binding for Ibrutinib...
September 10, 2016: Oncotarget
Stefania Fiorcari, Rossana Maffei, Valentina Audrito, Silvia Martinelli, Elisa Ten Hacken, Patrizia Zucchini, Giulia Grisendi, Leonardo Potenza, Mario Luppi, Jan A Burger, Silvia Deaglio, Roberto Marasca
In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton's tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features...
September 1, 2016: Oncotarget
Jingjing Wu, Christina Liu, Stella T Tsui, Delong Liu
Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and plays a major role in lymphoma genesis. Ibrutinib is the first-generation BTK inhibitor. Ibrutinib has off-target effects on EGFR, ITK, and Tec family kinases, which explains the untoward effects of ibrutinib. Resistance to ibrutinib was also reported. The C481S mutation in the BTK kinase domain was reported to be a major mechanism of resistance to ibrutinib. This review summarizes the clinical development of novel BTK inhibitors, ACP-196 (acalabrutinib), ONO/GS-4059, and BGB-3111...
2016: Journal of Hematology & Oncology
Joost C M Uitdehaag, Jeroen A D M de Roos, Martine B W Prinsen, Nicole Willemsen-Seegers, Judith R F de Vetter, Jelle Dylus, Antoon M van Doornmalen, Jeffrey Kooijman, Masaaki Sawa, Suzanne J C van Gerwen, Jos de Man, Rogier C Buijsman, Guido J R Zaman
Cancer cell line panels are important tools to characterize the in vitro activity of new investigational drugs. Here we present the inhibition profiles of 122 anti-cancer agents in proliferation assays with 44 or 66 genetically characterized cancer cell lines from diverse tumor tissues (Oncolines™). The library includes 29 cytotoxics, 68 kinase inhibitors and 11 epigenetic modulators. For 38 compounds this is the first comparative profiling in a cell line panel. By strictly maintaining optimized assay protocols, biological variation was kept to a minimum...
September 1, 2016: Molecular Cancer Therapeutics
Scott H Watterson, George V De Lucca, Qing Shi, Charles M Langevine, Qingjie Liu, Douglas G Batt, Myra Beaudoin Bertrand, Hua Gong, Jun Dai, Shiuhang Yip, Peng Li, Dawn Sun, Dauh-Rurng Wu, Chunlei Wang, Yingru Zhang, Sarah C Traeger, Mark A Pattoli, Stacey Skala, Lihong Cheng, Mary T Obermeier, Rodney Vickery, Lorell N Discenza, Celia J D'Arienzo, Yifan Zhang, Elizabeth Heimrich, Kathleen M Gillooly, Tracy L Taylor, Claudine Pulicicchio, Kim W McIntyre, Michael A Galella, Andy J Tebben, Jodi K Muckelbauer, ChiehYing Chang, Richard Rampulla, Arvind Mathur, Luisa Salter-Cid, Joel C Barrish, Percy H Carter, Aberra Fura, James R Burke, Joseph A Tino
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis...
October 13, 2016: Journal of Medicinal Chemistry
Alison Yeomans, Elizabeth Lemm, Sarah Wilmore, Breeze E Cavell, Beatriz Valle-Argos, Sergey Krysov, Marina Sanchez Hidalgo, Elodie Leonard, Anne E Willis, Francesco Forconi, Freda K Stevenson, Andrew J Steele, Mark J Coldwell, Graham Packham
Increased mRNA translation drives carcinogenesis and is an attractive target for the development of new anti-cancer drugs. In this work, we investigated effects of phenethylisothiocyanate (PEITC), a phytochemical with chemopreventive and anti-cancer activity, on mRNA translation. PEITC rapidly inhibited global mRNA translation in human breast cancer-derived MCF7 cells and mouse embryonic fibroblasts (MEFs). In addition to the known inhibitory effects of PEITC on mTORC1 activity, we demonstrate that PEITC increased eIF2α phosphorylation...
August 27, 2016: Oncotarget
Adam R Johnson, Pawan Bir Kohli, Arna Katewa, Emily Gogol, Lisa D Belmont, Regina Choy, Elicia Penuel, Luciana Burton, Charles Eigenbrot, Christine Yu, Daniel Fred Ortwine, Krista Bowman, Yvonne Franke, Christine Tam, Alberto Estevez, Kyle Mortara, Jiansheng Wu, Hong Li, May Lin, Philippe Bergeron, James J Crawford, Wendy B Young
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown impressive clinical efficacy in a range of B-cell malignancies, however acquired resistance has emerged and second generation therapies are now being sought. Ibrutinib is a covalent, irreversible inhibitor that modifies Cys481 in the ATP binding site of Btk and renders the enzyme inactive, thereby blocking B-cell receptor signal transduction. Not surprisingly, Cys481 is the most commonly mutated Btk residue in cases of acquired resistance to ibrutinib...
August 29, 2016: ACS Chemical Biology
Li Wei, Yu-Kai Su, Chien-Min Lin, Tsu-Yi Chao, Shang-Pen Huang, Thanh-Tuan Huynh, Hsun-Jin Jan, Jacqueline Whang-Peng, Jeng-Fong Chiou, Alexander T H Wu, Michael Hsiao
Standard interventions for glioma include surgery, radiation and chemotherapies but the prognosis for malignant cases such as glioblastoma multiforme remain grim. Even with targeted therapeutic agent, bevacitumab, malignant glioma often develops resistance and recurrence. Thus, developing alternative interventions (therapeutic targets, biomarkers) is urgently required. Bruton's tyrosine kinase (Btk) has been long implicated in B cell malignancies but surprisingly it has recently been shown to also play a tumorigenic role in solid tumors such as ovarian and prostate cancer...
August 24, 2016: Oncotarget
Andrea Haerzschel, Julie Catusse, Evelyn Hutterer, Manuela Paunovic, Katja Zirlik, Hermann Eibel, Peter W Krenn, Tanja N Hartmann, Meike Burger
Dysregulation of B cell receptor (BCR) signalling is a hallmark of chronic lymphocytic leukaemia (CLL) pathology, and targeting BCR pathway kinases has brought great therapeutic advances. Activation of the BCR in lymphoid organs has been associated with CLL cell proliferation and survival, leading to progressive disease. While these responses are mediated predominantly by IgM, the role of IgD is less clear. Seeking to uncover downstream consequences of individual and combined stimulation of the two BCR isotypes, we found an amplification of IgD expression and IgD-mediated calcium signalling by previous stimulation of IgM in CLL...
August 20, 2016: Annals of Hematology
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