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Btk inhibitor

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https://www.readbyqxmd.com/read/28328081/btk-inhibition-is-a-potent-approach-to-block-ige-mediated-histamine-release-in-human-basophils
#1
Dubravka Smiljkovic, Katharina Blatt, Gabriele Stefanzl, Yulia Dorofeeva, Cathrin Skrabs, Margarete Focke-Tejkl, Wolfgang R Sperr, Ulrich Jaeger, Rudolf Valenta, Peter Valent
BACKGROUND: Recent data suggest that Bruton's tyrosine kinase (BTK) is an emerging therapeutic target in IgE receptor (IgER) cross-linked basophils. METHODS: We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL-292, CNX-774) on IgE-dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and non-allergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU812 and the human mast cell line HMC-1...
March 22, 2017: Allergy
https://www.readbyqxmd.com/read/28315597/discovery-of-n-3-5-3-acrylamido-4-morpholine-4-carbonyl-phenyl-amino-1-methyl-6-oxo-1-6-dihydropyridin-3-yl-2-methylphenyl-4-tert-butyl-benzamide-chmfl-btk-01-as-a-highly-selective-irreversible-bruton-s-tyrosine-kinase-btk-inhibitor
#2
Qianmao Liang, Yongfei Chen, Kailin Yu, Cheng Chen, Shouxiang Zhang, Aoli Wang, Wei Wang, Hong Wu, Xiaochuan Liu, Beilei Wang, Li Wang, Zhenquan Hu, Wenchao Wang, Tao Ren, Shanchun Zhang, Qingsong Liu, Cai-Hong Yun, Jing Liu
Currently there are several irreversible BTK inhibitors targeting Cys481 residue under preclinical or clinical development. However, most of these inhibitors also targeted other kinases such as BMX, JAK3, and EGFR that bear the highly similar active cysteine residues. Through a structure-based drug design approach, we discovered a highly potent (IC50: 7 nM) irreversible BTK inhibitor compound 9 (CHMFL-BTK-01), which displayed a high selectivity profile in KINOMEscan (S score (35) = 0.00) among 468 kinases/mutants at the concentration of 1 μM...
March 2, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28315229/primary-central-nervous-system-lymphoma-essential-points-in-diagnosis-and-management
#3
REVIEW
Semra Paydas
Primary central nervous system lymphoma (PCNSL) is an extra-nodal non-Hodgkin lymphoma. PCNSL is defined as lymphoma involving the brain, leptomeninges, eyes, or spinal cord without evidence of lymphoma outside the CNS. Treatment includes induction with chemotherapy and consolidation with whole-brain radiotherapy or high-dose chemotherapy supported by autologous stem cell transplantation. High-dose methotrexate is the most important drug in cases with PCNSL, and this drug will be used in combination with small molecules, BTK inhibitors, new monoclonal antibodies, and checkpoint blockers...
April 2017: Medical Oncology
https://www.readbyqxmd.com/read/28298527/dual-inhibiton-of-bruton-s-tyrosine-kinase-and-phosphoinositide-3-kinase-p110%C3%AE-as-a-therapeutic-approach-to-treat-non-hodgkin-s-b-cell-malignancies
#4
Jennifer Alfaro, Felipe Perez de Arce, Sebastian Belmar, Glenda Fuentealba, Patricio Avila, Gonzalo Ureta, Camila Flores, Claudia Acuna, Luz Delgado, Diana Gaete, Brahmam Pujala, Anup Barde, Anjan K Nayak, Tvr Upendra, Dhananjay Patel, Shailender Chauhan, Vijay K Sharma, Stacy Kanno, Ramona G Almirez, David T Hung, Sarvajit Chakravarty, Roopa Rai, Sebastian Bernales, Kevin P Quinn, Son M Pham, Emma McCullagh
Although new targeted therapies such as ibrutinib and idelalisib have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors and possibly prolonging the duration of the response and reducing resistance...
March 15, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28295729/targeting-of-b-cell-receptor-signalling-in-b-cell-malignancies
#5
M Jerkeman, M Hallek, M Dreyling, C Thieblemont, E Kimby, L Staudt
Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma...
March 14, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28279528/discovery-and-evaluation-of-1h-pyrrolo-2-3-b-pyridine-based-selective-and-reversible-small-molecule-btk-inhibitors-for-the-treatment-of-rheumatoid-arthritis
#6
Mahesh Thakkar, Debnath Bhuniya, Rahul Kaduskar, Tanaji Mengawade, Keshav Naik, Videsh Salunkhe, Amit Bhalerao, Santosh Kurhade, Jagadeesh Mavinahalli, Vaibhav Jain, Rajkanth Petla, Satheesh Avaragolla, Swagatam Ray, Sreekanth Rouduri, Avinash Dhanave, Siddhartha De, Vishal Pathade, Ashwini Tambe, Amol A Raje, Vamsi Madgula, Sachin Joshi, Ahmed Nadeem, Madhu Bala, Dhananjay Umrani, Narayanan Hariharan, Bheemashankar Kulkarni, Kasim A Mookhtiar
In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA...
February 22, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28273548/bone-marrow-mesenchymal-stem-cells-regulate-stemness-of-multiple-myeloma-cell-lines-via-btk-signaling-pathway
#7
Pan Zhao, Yafang Chen, Zhijie Yue, Ying Yuan, Xiaofang Wang
Bone marrow mesenchymal stem cells (BM-MSCs) are key components of bone marrow microenvironment. Although the importances of BM-MSCs activation in myeloma cells growth, development, progression, angiogenesis are well known, their role in the regulation of myeloma stemness is unclear. In this study, myeloma cell lines (LP-1, U266) were co-cultured with BM-MSCs, we found that BM-MSCs could up-regulate the expression of key stemness genes and proteins (OCT4, SOX2, NANOG) and increase clonogenicity. Similarly, the mechanisms underlying the BM-MSC activation of myeloma stemness remain unclear...
February 24, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28265691/safety-pharmacokinetics-and-pharmacodynamics-of-bms-986142-a-novel-reversible-btk-inhibitor-in-healthy-participants
#8
Sun Ku Lee, Jun Xing, Ian M Catlett, Robert Adamczyk, Amber Griffies, Ang Liu, Bindu Murthy, Miroslawa Nowak
PURPOSE: BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton's tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. METHODS: In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5-900 mg) or multiple doses (25-350 mg, once daily for 14 days)...
March 6, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28265007/the-btk-inhibitor-ibrutinib-pci-32765-overcomes-paclitaxel-resistance-in-abcb1-and-abcc10-overexpressing-cells-and-tumors
#9
Hui Zhang, Atish S Patel, Yi-Jun Wang, Yun-Kai Zhang, Rishil J Kathawala, Long-Hui Qiu, Bhargav A Patel, Li-Hua Huang, Suneet Shukla, Dong-Hua Yang, Suresh V Ambudkar, Liwu Fu, Zhe-Sheng Chen
Paclitaxel is one of the most widely used antineoplastic drugs in clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP- Binding Cassette Subfamily B member 1 (ABCB1/P-gp) and Subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here we demonstrated that the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters...
March 6, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28254166/discovery-of-novel-btk-inhibitors-with-carboxylic-acids
#10
Xiaolei Gao, James Wang, Jian Liu, Deodial Guiadeen, Arto Krikorian, Sobhana Babu Boga, Abdul-Basit Alhassan, Oleg Selyutin, Wensheng Yu, Younong Yu, Rajan Anand, Shilan Liu, Chundao Yang, Hao Wu, Jiaqiang Cai, Alan Cooper, Hugh Zhu, Kevin Maloney, Ying-Duo Gao, Thierry O Fischmann, Jeremy Presland, My Mansueto, Zangwei Xu, Erica Leccese, Jie Zhang-Hoover, Ian Knemeyer, Charles G Garlisi, Nathan Bays, Peter Stivers, Philip E Brandish, Alexandra Hicks, Ronald Kim, Joeseph A Kozlowski
We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog...
November 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28245378/-effects-of-pci-32765-and-dasatinib-on-the-acute-lymphoblastic-leukemic-cells-and-their-mechanisms
#11
Yuan Deng, Shan-Dong Tao, Xin Zhang, Jing-Jing Ma, Zheng-Mei He, Yue Chen, Zhi-Kui Deng, Liang Yu
OBJECTIVE: To investigate the effects of Btk inhibitor (PCI-32765) and BCR-ABL tyrosine kinase inhibitor (Dasatinib) on proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines (Sup-B15, RS4;11) and the possible mechanism. METHODS: RS4;11 and Sup-B15 cells were treated with PCI-32765 and Dasatinib, the cell proliferation and apoptosis were detected by CCK-8, the Btk and other apoptotic proteins were detected by Western blot. RESULTS: PCI-32765 could inhibit the proliferation of RS4;11 and Sup-B15 cells in a dose-dependent manner, Sup-B15 cells were more sensitive to PCI-32765 than RS4;11 cells, their IC50 were 3 µmol/L and 8 µmol/L respectively, the difference between them was statistically significant (P<0...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28216434/human-nlrp3-inflammasome-activity-is-regulated-by-and-potentially-targetable-via-btk
#12
Xiao Liu, Tica Pichulik, Olaf-Oliver Wolz, Truong-Minh Dang, Andrea Stutz, Carly Dillen, Magno Delmiro Garcia, Helene Kraus, Sabine Dickhöfer, Ellen Daiber, Lisa Münzenmayer, Silke Wahl, Nikolaus Rieber, Jasmin Kümmerle-Deschner, Amir Yazdi, Mirita Franz-Wachtel, Boris Macek, Markus Radsak, Sebastian Vogel, Berit Schulte, Juliane Sarah Walz, Dominik Hartl, Eicke Latz, Stephan Stilgenbauer, Bodo Grimbacher, Lloyd Miller, Cornelia Brunner, Christiane Wolz, Alexander N R Weber
BACKGROUND: The Nod-like receptor, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and Bruton's tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively: NLRP3 senses exogenous and endogenous insults leading to inflammasome activation, which occurs spontaneously in Muckle-Wells Syndrome (MWS); BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified and clinically promising pharmacological targeting strategies remain elusive...
February 16, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28212557/using-high-sensitivity-sequencing-for-the-detection-of-mutations-in-btk-and-plc%C3%AE-2-genes-in-cellular-and-cell-free-dna-and-correlation-with-progression-in-patients-treated-with-btk-inhibitors
#13
Adam Albitar, Wanlong Ma, Ivan DeDios, Jeffrey Estella, Inhye Ahn, Mohammed Farooqui, Adrian Wiestner, Maher Albitar
Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib...
February 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28202459/il-4-cxcl12-loop-is-a-key-regulator-of-lymphoid-stroma-function-in-follicular-lymphoma
#14
Shubham Pandey, Frédéric Mourcin, Tony Marchand, Saba Nayar, Marion Guirriec, Céline Pangault, Céline Monvoisin, Patricia Amé-Thomas, Fabien Guilloton, Joelle Dulong, Mark Coles, Thierry Fest, Anja Mottok, Francesca Barone, Karin Tarte
Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by the accumulation of germinal center-derived malignant B cells engaged in a bidirectional crosstalk with their supportive microenvironment in invaded lymph nodes (LN) and bone marrow (BM). T follicular helper cells (TFH) and infiltrating stromal cells have been shown to favor FL B-cell growth but the mechanisms of their protumoral effect and how LN/BM microenvironment is converted into a lymphoma-permissive cell niche remain poorly understood...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#15
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28185174/current-treatment-of-chronic-lymphocytic-leukemia
#16
REVIEW
Krzysztof Jamroziak, Bartosz Puła, Jan Walewski
A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28182323/ibrutinib-associated-bleeding-pathogenesis-management-and-risk-reduction-strategies
#17
REVIEW
Joseph J Shatzel, Sven R Olson, Derrick L Tao, Owen J T McCarty, Alexey V Danilov, Thomas G DeLoughery
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared to standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently minimal data to guide clinicians regarding the use of ibrutinib in patients at high risk for bleeding or on anticoagulant or antiplatelet therapy...
February 9, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28178345/pi3k%C3%AE-inhibitor-idelalisib-in-combination-with-btk-inhibitor-ono-gs-4059-in-diffuse-large-b-cell-lymphoma-with-acquired-resistance-to-pi3k%C3%AE-and-btk-inhibitors
#18
Anella Yahiaoui, Sarah A Meadows, Rick A Sorensen, Zhi-Hua Cui, Kathleen S Keegan, Robert Brockett, Guang Chen, Christophe Quéva, Li Li, Stacey L Tannheimer
Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma...
2017: PloS One
https://www.readbyqxmd.com/read/28147336/dual-inhibition-of-histone-deacetylases-and-phosphoinositide-3-kinase-enhances-therapeutic-activity-against-b-cell-lymphoma
#19
Patrizia Mondello, Enrico Derenzini, Zahra Asgari, John Philip, Elliott J Brea, Venkatraman Seshan, Ronald C Hendrickson, Elisa de Stanchina, David A Scheinberg, Anas Younes
Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin...
January 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28146266/how-i-manage-patients-with-hairy-cell-leukaemia
#20
REVIEW
Philip A Thompson, Farhad Ravandi
Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition...
February 1, 2017: British Journal of Haematology
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