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https://www.readbyqxmd.com/read/28096090/how-i-manage-ibrutinib-refractory-chronic-lymphocytic-leukemia
#1
Jennifer A Woyach
The introduction of the Bruton's Tyrosine Kinase inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia. Although responses have been durable in the majority of patients, relapses do occur, especially in the high risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes following ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28092987/emerging-treatment-approaches-for-myeloma-related-bone-disease
#2
Maria Gavriatopoulou, Meletios A Dimopoulos, Efstathios Kastritis, Evangelos Terpos
Multiple myeloma is characterized by the presence of osteolytic lesions that leads to devastating skeletal-related events in the majority of patients. Myeloma bone disease is attributed to increased osteoclastic and suppressed osteoblastic activity. Areas covered: Bisphosphonates remain the main treatment option, however they have limitations on their own. Understanding the pathogenesis of myeloma bone disease may provide a roadmap for new therapeutic approaches. The pathway of RANKRANKLOPG pathway has revealed denosumab, a monoclonal antibody targeting RANKL as a novel emerging therapy for myeloma-related bone disease...
January 17, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28088788/dual-syk-jak-inhibition-overcomes-ibrutinib-resistance-in-chronic-lymphocytic-leukemia-cerdulatinib-but-not-ibrutinib-induces-apoptosis-of-tumor-cells-protected-by-the-microenvironment
#3
Ailin Guo, Pin Lu, Greg Coffey, Pamela Conley, Anjali Pandey, Y Lynn Wang
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28073005/simultaneous-inhibition-of-pi3k%C3%AE-and-pi3k%C3%AE-induces-abc-dlbcl-regression-by-blocking-bcr-dependent-and-independent-activation-of-nf-%C3%AE%C2%BAb-and-akt
#4
Juliane Paul, Maurice Soujon, Antje M Wengner, Sabine Zitzmann-Kolbe, Andrea Sturz, Katja Haike, Koh Hui Keng Magdalene, Sze Huey Tan, Martin Lange, Soo Yong Tan, Dominik Mumberg, Soon Thye Lim, Karl Ziegelbauer, Ningshu Liu
Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79(mut), CARD11(mut), TNFAIP3(mut), or MYD88(mut)...
January 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28062735/the-ability-of-btk-inhibitors-to-sequester-y551-and-prevent-phosphorylation-determines-potency-for-inhibition-of-fcr-but-not-b-cell-receptor-signaling
#5
Andrew T Bender, Anna Gardberg, Albertina Pereira, Theresa Johenson, Yin Wu, Roland Grenningloh, Jared Head, Federica Morandi, Philipp Haselmayer, Lesley Liu-Bujalski
Bruton's tyrosine kinase (Btk) is expressed in a variety of hematopoietic cells. Btk has been demonstrated to regulate signaling downstream of the B cell receptor (BCR), Fc receptors (FcR), and toll like receptors (TLRs). Btk has become an attractive drug target as Btk inhibition may provide significant efficacy by blocking multiple disease mechanisms simultaneously. Consequently, a large number of Btk inhibitors have been developed. The compounds have diverse binding modes and both reversible and irreversible inhibitors have been developed...
January 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28056160/discovery-of-a-potent-btk-inhibitor-with-a-novel-binding-mode-using-parallel-selections-with-a-dna-encoded-chemical-library
#6
John W Cuozzo, Paolo A Centrella, Diana Gikunju, Sevan Habeshian, Christopher D Hupp, Anthony D Keefe, Eric A Sigel, Holly H Soutter, Heather A Thomson, Ying Zhang, Matthew A Clark
We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA encoded library of over 110 million compounds using multiple parallel selection conditions including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building-block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP and another enriched at both high and low concentrations of BTK and was not competitive with ATP...
January 5, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28036258/epstein-barr-virus-ebna2-directs-doxorubicin-resistance-of-b-cell-lymphoma-through-ccl3-and-ccl4-mediated-activation-of-nf-%C3%AE%C2%BAb-and-btk
#7
Joo Hyun Kim, Won Seog Kim, Jung Yong Hong, Kung Ju Ryu, Seok Jin Kim, Chaehwa Park
Epstein-Barr virus (EBV)-encoded nuclear antigen, EBNA2, expressed in EBV-infected B lymphocytes is critical for lymphoblastoid cell growth. Microarray profiling and cytokine array screening revealed that EBNA2 is associated with upregulation of the chemokines CCL3 and CCL4 in lymphoma cells. Depletion or inactivation of CCL3 or CCL4 sensitized DLBCL cells to doxorubicin. Our results indicate that EBV influences cell survival via an autocrine mechanism whereby EBNA2 increases CCL3 and CCL4, which in turn activate the Btk and NF-κB pathways, contributing to doxorubicin resistance of B lymphoma cells...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28034907/comparison-of-acalabrutinib-a-selective-bruton-tyrosine-kinase-inhibitor-with-ibrutinib-in-chronic-lymphocytic-leukemia-cells
#8
Viralkumar Patel, Kumudha Balakrishnan, Elena Bibikova, Mary Ayres, Michael J Keating, William Wierda, Varsha Gandhi
PURPOSE: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor designed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL...
December 29, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28031181/ibrutinib-inhibits-pre-bcr-b-cell-acute-lymphoblastic-leukemia-progression-by-targeting-btk-and-blk
#9
Ekaterina Kim, Christian Hurtz, Stefan Koehrer, Zhiqiang Wang, Sriram Balasubramanian, Betty Y Chang, Markus Müschen, R Eric Davis, Jan A Burger
Targeting B cell receptor (BCR) signaling is a successful therapeutic strategy in mature B cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR(+) B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR(+) ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations...
December 28, 2016: Blood
https://www.readbyqxmd.com/read/28025004/mitigation-of-reactive-metabolite-formation-for-a-series-of-3-amino-2-pyridone-inhibitors-of-bruton-s-tyrosine-kinase-btk
#10
Yan Lou, Francisco Lopez, Yongying Jiang, Xiaochun Han, Chris Brotherton, Roland Billedeau, Steve Gabriel, Shelly Gleason, David M Goldstein, Ramona Hilgenkamp, Buelent Kocer, Lucja Orzechowski, Jenny Tan, Peter Wovkulich, Bo Wen, David Fry, Paola Di Lello, Lucy Chen, Fang-Jie Zhang, Jennifer Fretland, Anjali Nangia, Tian Yang, Timothy D Owens
Reactive metabolites have been putatively linked to many adverse drug reactions including idiosyncratic toxicities for a number of drugs with black box warnings or withdrawn from the market. Therefore, it is desirable to minimize the risk of reactive metabolite formation for lead molecules in optimization, in particular for non-life threatening chronic disease, to maximize benefit to risk ratio. This article describes our effort in addressing reactive metabolite issues for a series of 3-amino-2-pyridone inhibitors of BTK, e...
December 2, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28011673/distinct-patterns-of-b-cell-receptor-signaling-in-non-hodgkins-lymphomas-identified-by-single-cell-profiling
#11
June H Myklebust, Joshua Brody, Holbrook E Kohrt, Arne Kolstad, Debra K Czerwinski, Sébastien Wälchli, Michael R Green, Gunhild Trøen, Knut Liestøl, Klaus Beiske, Roch Houot, Jan Delabie, Ash A Alizadeh, Jonathan M Irish, Ronald Levy
Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkins' lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phospho-specific flow cytometry to obtain signaling profiles of malignant B cells from 95 patients representing 4 types of NHL, revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most of the measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels...
December 23, 2016: Blood
https://www.readbyqxmd.com/read/27994757/discovery-of-pyrazolopyrimidine-derivatives-as-novel-dual-inhibitors-of-btk-and-pi3k%C3%AE
#12
Brahmam Pujala, Anil K Agarwal, Sandip Middya, Monali Banerjee, Arjun Surya, Anjan K Nayak, Ashu Gupta, Sweta Khare, Rambabu Guguloth, Nitin A Randive, Bharat U Shinde, Anamika Thakur, Dhananjay I Patel, Mohd Raja, Michael J Green, Jennifer Alfaro, Patricio Avila, Felipe Pérez de Arce, Ramona G Almirez, Stacy Kanno, Sebastián Bernales, David T Hung, Sarvajit Chakravarty, Emma McCullagh, Kevin P Quinn, Roopa Rai, Son M Pham
The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27994736/discovery-of-novel-bruton-s-tyrosine-kinase-btk-inhibitors-bearing-a-n-9-diphenyl-9h-purin-2-amine-scaffold
#13
Yang Ge, Yue Jin, Changyuan Wang, Jianbin Zhang, Zeyao Tang, Jinyong Peng, Kexin Liu, Yanxia Li, Youwen Zhou, Xiaodong Ma
Based on the pyrimidine skeleton of EGFR(T790M) inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 μM...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27993968/mechanisms-of-acquired-drug-resistance-to-the-hdac6-selective-inhibitor-ricolinostat-reveals-rational-drug-drug-combination-with-ibrutinib
#14
Jennifer E Amengual, Sathyen A Prabhu, Maximilian Lombardo, Kelly M Zullo, Paul M Johannet, Yulissa Gonzalez, Luigi Scotto, Xavier Jirau-Serrano, Ying Wei, Jimmy K Duong, Renu Nandakumar, Serge Cremers, Akanksha Verma, Olivier Elemento, Owen A O'Connor
PURPOSE: Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first in class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. EXPERIMENTAL DESIGN: The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line...
December 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27960302/metabolically-labile-fumarate-esters-impart-kinetic-selectivity-to-irreversible-inhibitors
#15
Balyn W Zaro, Landon R Whitby, Kenneth M Lum, Benjamin F Cravatt
Electrophilic small molecules are an important class of chemical probes and drugs that produce biological effects by irreversibly modifying proteins. Examples of electrophilic drugs include covalent kinase inhibitors that are used to treat cancer and the multiple sclerosis drug dimethyl fumarate. Optimized covalent drugs typically inactivate their protein targets rapidly in cells, but ensuing time-dependent, off-target protein modification can erode selectivity and diminish the utility of reactive small molecules as chemical probes and therapeutics...
December 14, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27956037/design-and-synthesis-of-phosphoryl-substituted-diphenylpyrimidines-pho-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-targeted-treatment-of-b-lymphoblastic-leukemia-cell-lines
#16
Yang Ge, Haijun Yang, Changyuan Wang, Qiang Meng, Lei Li, Huijun Sun, Yuhong Zhen, Kexin Liu, Yanxia Li, Xiaodong Ma
A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17μM and 6.69μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree...
January 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27923841/biological-and-clinical-relevance-of-associated-genomic-alterations-in-myd88-l265p-and-non-l265p-mutated-diffuse-large-b-cell-lymphoma-analysis-of-361-cases
#17
Sydney Dubois, Pierre-Julien Viailly, Elodie Bohers, Philippe Bertrand, Philippe Ruminy, Vinciane Marchand, Catherine Maingonnat, Sylvain Mareschal, Jean-Michel Picquenot, Dominique Penther, Jean-Philippe Jais, Bruno Tesson, Pauline Peyrouze, Martin Figeac, Fabienne Desmots, Thierry Fest, Corinne Haioun, Thierry Lamy, Christiane Copie-Bergman, Bettina Fabiani, Richard Delarue, Frederic Peyrade, Marc André, Nicolas Ketterer, Karen Leroy, Gilles Salles, Thierry J Molina, Herve Tilly, Fabrice Jardin
PURPOSE: MYD88 mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of Activated B-Cell like (ABC) Diffuse Large B Cell Lymphoma (DLBCL), leading to constitutive NFkB pathway activation. The aim of this study was to examine the distinct genomic profiles of MYD88 mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants. EXPERIMENTAL DESIGN: A cohort of 361 DLBCL cases (94 MYD88 mutant and 267 MYD88 wild-type) was submitted to next generation sequencing (NGS) focusing on 34 genes in order to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses...
December 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27918558/quantitating-drug-target-engagement-in-single-cells-in-vitro-and-in-vivo
#18
J Matthew Dubach, Eunha Kim, Katherine Yang, Michael Cuccarese, Randy J Giedt, Labros G Meimetis, Claudio Vinegoni, Ralph Weissleder
Quantitation of drug target engagement in single cells has proven to be difficult, often leaving unanswered questions in the drug development process. We found that intracellular target engagement of unlabeled new therapeutics can be quantitated using polarized microscopy combined with competitive binding of matched fluorescent companion imaging probes. We quantitated the dynamics of target engagement of covalent BTK inhibitors, as well as reversible PARP inhibitors, in populations of single cells using a single companion imaging probe for each target...
February 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/27912175/structural-optimization-of-diphenylpyrimidine-derivatives-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-leukemia-cell-lines
#19
Dan Zhao, Shanshan Huang, Menghua Qu, Changyuan Wang, Zhihao Liu, Zhen Li, Jinyong Peng, Kexin Liu, Yanxia Li, Xiaodong Ma, Xiaohong Shu
A new series of diphenylpyrimidine derivatives (DPPYs) bearing various aniline side chains at the C-2 position of pyrimidine core were synthesized as potent BTK inhibitors. Most of these inhibitors displayed improved activity against B leukemia cell lines compared with lead compound spebrutinib. Subsequent studies showed that the peculiar inhibitor 7j, with IC50 values of 10.5 μM against Ramos cells and 19.1 μM against Raji cells, also displayed slightly higher inhibitory ability than the novel agent ibrutinib...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27909342/ristocetin-induced-platelet-aggregation-for-monitoring-of-bleeding-tendency-in-cll-treated-with-ibrutinib
#20
L Kazianka, C Drucker, C Skrabs, W Thomas, T Melchardt, S Struve, M Bergmann, P B Staber, E Porpaczy, C Einberger, M Heinz, A Hauswirth, M Raderer, I Pabinger, R Thalhammer, A Egle, C-M Wendtner, G Follows, G Hoermann, P Quehenberger, B Jilma, U Jaeger
Bleeding because of impaired platelet function is a major side effect of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. We quantitatively assessed ristocetin-induced platelet aggregation (RIPA) in 64 patients with chronic lymphocytic leukemia (CLL) under ibrutinib at 287 time points. Eighty-seven bleeding episodes in 39 patients were registered (85 Common Toxicity Criteria (CTC) grade 1 or 2, 2 CTC grade 3) during a median observation period of 10.9 months. At times of bleeding, RIPA values were significantly lower (14 vs 28 U; P<0...
December 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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