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https://www.readbyqxmd.com/read/28343126/pi3k-signaling-in-cancer-beyond-akt
#1
REVIEW
Evan C Lien, Christian C Dibble, Alex Toker
The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K...
March 23, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28337328/structure-activity-relationship-study-of-ql47-a-broad-spectrum-antiviral-agent
#2
Yanke Liang, Melissanne de Wispelaere, Margot Carocci, Qingsong Liu, Jinhua Wang, Priscilla L Yang, Nathanael S Gray
Here we report the structure-activity relationship (SAR) investigations of QL-XII-47 (QL47), a compound that possesses broad-spectrum antiviral activity against dengue virus and other RNA viruses. A medicinal chemistry campaign initiated from QL47, a previously reported covalent BTK inhibitor, to derive YKL-04-085, which is devoid of any kinase activity when screened against a panel of 468 kinases and with improved pharmacokinetic properties. Both QL47 and YKL-04-085 are potent inhibitors of viral translation and exhibit cellular antiviral activity at 35-fold lower concentrations relative to inhibition of host-cell proliferation...
March 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28328081/btk-inhibition-is-a-potent-approach-to-block-ige-mediated-histamine-release-in-human-basophils
#3
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
#4
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
#5
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/28304004/x-linked-agammaglobulinemia-first-case-with-bruton-tyrosine-kinase-mutation-from-pakistan
#6
Samreen Kulsom Zaidi, Sonia Qureshi, Farah Naz Qamar
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency with more than 600 mutations in Bruton tyrosine kinase (Bkt) gene which are responsible for early-onset agammaglobulinemia and repeated infections. Herein we present a case of a 3-year-old boy with history of repeated diarrhoea and an episode of meningoencephalitis with hemiplegia. The workup showed extremely low levels of immunoglobulin with low CD+19 cells. Genetic analysis showed Btk mutation 18 c.1883delCp.T628fs. To the best of our knowledge this is the first report of a case of XLA confirmed by molecular technique from Pakistan...
March 2017: JPMA. the Journal of the Pakistan Medical Association
https://www.readbyqxmd.com/read/28303702/studies-on-the-quality-nutrition-in-women-with-polycystic-ovary-syndrome-pcos
#7
Małgorzata Szczuko, Patrycja Sankowska, Marta Zapałowska-Chwyć, Paweł Wysokiński
Background: Polycystic ovary syndrome (PCOS) manifests itself with various symptoms, therefore it interests representatives of many medical specializations: general practitioners, gynecologists, endocrinologists, dermatologists, cardiologists and those who deal with metabolic disorders, such as dieticians. Objective: The aim of this study was perform the qualitative assessment of components of diets of women with PCOS as one of the major factor contributing to the disease...
2017: Roczniki Państwowego Zakładu Higieny
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
#8
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
#9
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/28294689/genomics-signaling-and-treatment-of-waldenstr%C3%A3-m-macroglobulinemia
#10
Zachary R Hunter, Guang Yang, Lian Xu, Xia Liu, Jorge J Castillo, Steven P Treon
Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88...
February 13, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28290728/diffuse-large-b-cell-lymphoma-in-the-elderly-standard-treatment-and-new-perspectives
#11
Chiappella Annalisa, Alessia Castellino, Maura Nicolosi, Elisa Santambrogio, Umberto Vitolo
Diffuse large B-cell lymphoma (DLBCL) is the most common histotype in non Hodgkin lymphoma, with a peak incidence in the sixth decade. The standard treatment for elderly FIT DLBCL patients is Rituximab-CHOP; in unfit and frail patients, chemotherapy at reduced intensity should be considered. Areas covered: In this article, we will review use of standard therapies and new drugs investigated such as immonomudulating agents (IMiDs), Bruton Tyrosine Kinase (BTK), in fit, unfit, frail and very elderly DLCBL patients...
March 14, 2017: Expert Review of Hematology
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
#12
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/28275136/distinct-and-overlapping-functions-of-tec-kinase-and-btk-in-b-cell-receptor-signaling
#13
Marjolein J W de Bruijn, Jasper Rip, Esmee K van der Ploeg, Lars W van Greuningen, Van T B Ta, Laurens P Kil, Anton W Langerak, Guus F Rimmelzwaan, Wilfried Ellmeier, Rudi W Hendriks, Odilia B J Corneth
The Tec tyrosine kinase is expressed in many cell types, including hematopoietic cells, and is a member of the Tec kinase family that also includes Btk. Although the role of Btk in B cells has been extensively studied, the role of Tec kinase in B cells remains largely unclear. It was previously shown that Tec kinase has the ability to partly compensate for loss of Btk activity in B cell differentiation, although the underlying mechanism is unknown. In this study, we confirm that Tec kinase is not essential for normal B cell development when Btk is present, but we also found that Tec-deficient mature B cells showed increased activation, proliferation, and survival upon BCR stimulation, even in the presence of Btk...
March 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28273548/bone-marrow-mesenchymal-stem-cells-regulate-stemness-of-multiple-myeloma-cell-lines-via-btk-signaling-pathway
#14
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/28272351/methyl-gallate-inhibits-osteoclast-formation-and-function-by-suppressing-akt-and-btk-plc%C3%AE-2-ca-2-signaling-and-prevents-lipopolysaccharide-induced-bone-loss
#15
Jong Min Baek, Ju-Young Kim, Chang Hoon Lee, Kwon-Ha Yoon, Myeung Su Lee
In the field of bone research, various natural derivatives have emerged as candidates for osteoporosis treatment by targeting abnormally elevated osteoclastic activity. Methyl gallate, a plant-derived phenolic compound, is known to have numerous pharmacological effects against inflammation, oxidation, and cancer. Our purpose was to explore the relation between methyl gallate and bone metabolism. Herein, we performed screening using methyl gallate by tartrate resistant acid phosphatase (TRAP) staining and revealed intracellular mechanisms responsible for methyl gallate-mediated regulation of osteoclastogenesis by Western blotting and quantitative reverse transcription polymerase chain reaction (RT-PCR)...
March 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28265691/safety-pharmacokinetics-and-pharmacodynamics-of-bms-986142-a-novel-reversible-btk-inhibitor-in-healthy-participants
#16
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
#17
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
#18
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
#19
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/28235842/acquired-mutations-associated-with-ibrutinib-resistance-in-waldenstrom-macroglobulinemia
#20
Lian Xu, Nicholas Tsakmaklis, Guang Yang, Jiaji G Chen, Xia Liu, Maria Demos, Amanda Kofides, Christopher J Patterson, Kirsten Meid, Joshua Gustine, Toni Dubeau, M Lia Palomba, Ranjana Advani, Jorge J Castillo, Richard R Furman, Zachary R Hunter, Steven P Treon
Ibrutinib produces high response rates and durable remissions in Waldenstrom's Macroglobulinemia (WM) that are impacted by MYD88 and CXCR4(WHIM) mutations. Disease progression can develop on ibrutinib, though the molecular basis remains to be clarified. We sequenced sorted CD19(+) lymphoplasmacytic cells from 6 WM patients who progressed after achieving major responses on ibrutinib using Sanger, TA cloning and sequencing, and highly sensitive and specific AS-PCR assays that we developed for BTK mutations. AS-PCR assays were used to screen patients with and without progressive disease on ibrutinib, and ibrutinib-naïve disease...
February 24, 2017: Blood
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