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https://www.readbyqxmd.com/read/29778502/hematopoietic-stem-cell-transplantation-for-progressive-combined-immunodeficiency-and-lymphoproliferation-in-activated-pi3k-delta-syndrome-type-1
#1
Tsubasa Okano, Kohsuke Imai, Yuki Tsujita, Noriko Mitsuiki, Kenichi Yoshida, Chikako Kamae, Kenichi Honma, Kanako Mitsui-Sekinaka, Yujin Sekinaka, Tamaki Kato, Katsuyuki Hanabusa, Eri Endo, Takehiro Takashima, Haruka Hiroki, Tzu-Wen Yeh, Keisuke Tanaka, Masakazu Nagahori, Ikuya Tsuge, Yuki Bando, Fuminori Iwasaki, Yoshiaki Shikama, Masami Inoue, Tomiko Kimoto, Naohiko Moriguchi, Yuki Yuza, Takashi Kaneko, Kyoko Suzuki, Tomoyo Matsubara, Yoshihiro Maruo, Tomoaki Kunitsu, Tomoko Waragai, Hideki Sano, Yuko Hashimoto, Kazuhiro Tasaki, Osamu Suzuki, Toshihiko Shirakawa, Motohiro Kato, Toru Uchiyama, Masataka Ishimura, Tetsuzo Tauchi, Hiroshi Yagasaki, Shiann-Tarng Jou, Hsin-Hui Yu, Hirokazu Kanegane, Sven Kracker, Anne Durandy, Daiei Kojima, Hideki Muramatsu, Taizo Wada, Yuzaburo Inoue, Hidetoshi Takada, Seiji Kojima, Seishi Ogawa, Osamu Ohara, Shigeaki Nonoyama, Tomohiro Morio
BACKGROUND: Activated phosphatidylinositol-3-OH kinase-delta (PI3Kδ) syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory infections, lymphoid hyperplasia, and herpesviridae infections due to germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) may be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, method, and outcomes of HSCT for APDS1 remain undefined...
May 17, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29651336/pi3k-p38-and-jak-stat-signalling-in-bronchial-tissue-from-patients-with-asthma-following-allergen-challenge
#2
Thomas Southworth, Sarah Mason, Alan Bell, Isabel Ramis, Marta Calbet, Anna Domenech, Neus Prats, Montserrat Miralpeix, Dave Singh
Background: Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known. Methods: We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry...
2018: Biomarker Research
https://www.readbyqxmd.com/read/29617050/transient-antagonism-of-anti-cd20-monoclonal-antibodies-and-pi3k-inhibitor-idelalisib-in-dlbcl-cell-lines
#3
Anna-Katharina Zoellner, Nico Peter, Yvonne Zimmermann, Grit Hutter, Wolfgang Hiddemann, Martin Dreyling
INTRODUCTION: PI3K inhibitors are evaluated for relapsed and refractory Diffuse large B-cell lymphoma (DLBCL) patients. OBJECTIVE: As rituximab has shown to influence B-cell receptor (BCR) signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib. METHODS: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib...
April 4, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/28947947/discovery-of-cdz173-leniolisib-representing-a-structurally-novel-class-of-pi3k-delta-selective-inhibitors
#4
Klemens Hoegenauer, Nicolas Soldermann, Frédéric Zécri, Ross S Strang, Nadege Graveleau, Romain M Wolf, Nigel G Cooke, Alexander B Smith, Gregory J Hollingworth, Joachim Blanz, Sascha Gutmann, Gabriele Rummel, Amanda Littlewood-Evans, Christoph Burkhart
The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and β isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties...
September 14, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28754522/finding-patients-using-similarity-measures-in-a-rare-diseases-oriented-clinical-data-warehouse-dr-warehouse-and-the-needle-in-the-needle-stack
#5
Nicolas Garcelon, Antoine Neuraz, Vincent Benoit, Rémi Salomon, Sven Kracker, Felipe Suarez, Nadia Bahi-Buisson, Smail Hadj-Rabia, Alain Fischer, Arnold Munnich, Anita Burgun
OBJECTIVE: In the context of rare diseases, it may be helpful to detect patients with similar medical histories, diagnoses and outcomes from a large number of cases with automated methods. To reduce the time to find new cases, we developed a method to find similar patients given an index case leveraging data from the electronic health records. MATERIALS AND METHODS: We used the clinical data warehouse of a children academic hospital in Paris, France (Necker-Enfants Malades), containing about 400,000 patients...
September 2017: Journal of Biomedical Informatics
https://www.readbyqxmd.com/read/28713374/the-selective-phosphoinoside-3-kinase-p110%C3%AE-inhibitor-ipi-3063-potently-suppresses-b-cell-survival-proliferation-and-differentiation
#6
Honyin Chiu, Sharmila Mallya, Phuongthao Nguyen, Annie Mai, Leandra V Jackson, David G Winkler, Jonathan P DiNitto, Erin E Brophy, Karen McGovern, Jeffery L Kutok, David A Fruman
The class I phosphoinoside-3-kinases (PI3Ks) are important enzymes that relay signals from cell surface receptors to downstream mediators driving cellular functions. Elevated PI3K signaling is found in B cell malignancies and lymphocytes of patients with autoimmune disease. The p110δ catalytic isoform of PI3K is a rational target since it is critical for B lymphocyte development, survival, activation, and differentiation. In addition, activating mutations in PIK3CD encoding p110δ cause a human immunodeficiency known as activated PI3K delta syndrome...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28645939/combined-btk-and-pi3k%C3%AE-inhibition-with-acalabrutinib-and-acp-319-improves-survival-and-tumor-control-in-cll-mouse-model
#7
Carsten U Niemann, Helena I Mora-Jensen, Eman L Dadashian, Fanny Krantz, Todd Covey, Shih-Shih Chen, Nicholas Chiorazzi, Raquel Izumi, Roger Ulrich, Brian J Lannutti, Adrian Wiestner, Sarah E M Herman
Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of Bruton tyrosine kinase (BTK) and PI3Kδ is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon, and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3Kδ and BTK inhibitors. Experimental Design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3Kδ inhibitor ACP-319 in vivo We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL...
October 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28185174/current-treatment-of-chronic-lymphocytic-leukemia
#8
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/28167755/conformational-disruption-of-pi3k%C3%AE-regulation-by-immunodeficiency-mutations-in-pik3cd-and-pik3r1
#9
Gillian L Dornan, Braden D Siempelkamp, Meredith L Jenkins, Oscar Vadas, Carrie L Lucas, John E Burke
Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in either the leukocyte-restricted p110δ catalytic ( PIK3CD ) subunit or the ubiquitously expressed p85α regulatory ( PIK3R1 ) subunit of class IA phosphoinositide 3-kinases (PI3Ks). There are two classes of APDS: APDS1 that arises from p110δ mutations that are analogous to oncogenic mutations found in the broadly expressed p110α subunit and APDS2 that occurs from a splice mutation resulting in p85α with a central deletion (Δ434-475)...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27847301/hematopoietic-stem-cell-transplant-in-patients-with-activated-pi3k-delta-syndrome
#10
Zohreh Nademi, Mary A Slatter, Christopher C Dvorak, Benedicte Neven, Alain Fischer, Felipe Suarez, Claire Booth, Kanchan Rao, Alexandra Laberko, Julia Rodina, Yves Bertrand, Sylwia Kołtan, Robert Dębski, Terence Flood, Mario Abinun, Andrew R Gennery, Sophie Hambleton, Stephan Ehl, Andrew J Cant
No abstract text is available yet for this article.
November 12, 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/27816514/discovery-of-novel-pyrrolidineoxy-substituted-heteroaromatics-as-potent-and-selective-pi3k-delta-inhibitors-with-improved-physicochemical-properties
#11
Klemens Hoegenauer, Nicolas Soldermann, Christina Hebach, Gregory J Hollingworth, Ian Lewis, Anette von Matt, Alexander B Smith, Romain M Wolf, Rainer Wilcken, Dorothea Haasen, Christoph Burkhart, Frédéric Zécri
In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ...
December 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27784673/silencing-c-myc-translation-as-a-therapeutic-strategy-through-targeting-pi3k%C3%AE-and-ck1%C3%AE%C2%B5-in-hematological-malignancies
#12
Changchun Deng, Mark R Lipstein, Luigi Scotto, Xavier O Jirau Serrano, Michael A Mangone, Shirong Li, Jeremie Vendome, Yun Hao, Xiaoming Xu, Shi-Xian Deng, Ronald B Realubit, Nicholas P Tatonetti, Charles Karan, Suzanne Lentzsch, David A Fruman, Barry Honig, Donald W Landry, Owen A O'Connor
Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells...
January 5, 2017: Blood
https://www.readbyqxmd.com/read/27660855/discovery-of-orally-efficacious-phosphoinositide-3-kinase-%C3%AE-inhibitors-with-improved-metabolic-stability
#13
Leena Patel, Jayaraman Chandrasekhar, Jerry Evarts, Kristen Forseth, Aaron C Haran, Carmen Ip, Adam Kashishian, Musong Kim, David Koditek, Sandy Koppenol, Latesh Lad, Eve-Irene Lepist, Mary E McGrath, Stephane Perreault, Kamal D Puri, Armando G Villaseñor, John R Somoza, Bart H Steiner, Joseph Therrien, Jennifer Treiberg, Gary Phillips
Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.
October 3, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27563400/discovery-and-pharmacological-characterization-of-novel-quinazoline-based-pi3k-delta-selective-inhibitors
#14
Klemens Hoegenauer, Nicolas Soldermann, Frédéric Stauffer, Pascal Furet, Nadege Graveleau, Alexander B Smith, Christina Hebach, Gregory J Hollingworth, Ian Lewis, Sascha Gutmann, Gabriele Rummel, Mark Knapp, Romain M Wolf, Joachim Blanz, Roland Feifel, Christoph Burkhart, Frédéric Zécri
Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction-reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated...
August 11, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27040704/the-pi3k-pathway-clinical-inhibition-in-chronic-lymphocytic-leukemia
#15
REVIEW
Jennifer R Brown
Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including chronic lymphocytic leukemia (CLL). The δ isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform that shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis...
April 2016: Seminars in Oncology
https://www.readbyqxmd.com/read/26961147/combination-of-the-mek-inhibitor-pimasertib-with-btk-or-pi3k-delta-inhibitors-is-active-in-preclinical-models-of-aggressive-lymphomas
#16
E Gaudio, C Tarantelli, I Kwee, C Barassi, E Bernasconi, A Rinaldi, M Ponzoni, L Cascione, A Targa, A Stathis, S Goodstal, E Zucca, F Bertoni
BACKGROUND: Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models. MATERIALS AND METHODS: Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone...
June 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/26301626/optimization-of-novel-indazoles-as-highly-potent-and-selective-inhibitors-of-phosphoinositide-3-kinase-%C3%AE-for-the-treatment-of-respiratory-disease
#17
Kenneth Down, Augustin Amour, Ian R Baldwin, Anthony W J Cooper, Angela M Deakin, Leigh M Felton, Stephen B Guntrip, Charlotte Hardy, Zoë A Harrison, Katherine L Jones, Paul Jones, Suzanne E Keeling, Joelle Le, Stefano Livia, Fiona Lucas, Christopher J Lunniss, Nigel J Parr, Ed Robinson, Paul Rowland, Sarah Smith, Daniel A Thomas, Giovanni Vitulli, Yoshiaki Washio, J Nicole Hamblin
Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.
September 24, 2015: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26193078/microenvironment-interactions-and-b-cell-receptor-signaling-in-chronic-lymphocytic-leukemia-implications-for-disease-pathogenesis-and-treatment
#18
REVIEW
Elisa Ten Hacken, Jan A Burger
Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL...
March 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/25993154/management-of-chronic-lymphocytic-leukemia
#19
REVIEW
Stephan Stilgenbauer, Richard R Furman, Clive S Zent
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually diagnosed in asymptomatic patients with early-stage disease. The standard management approach is careful observation, irrespective of risk factors unless patients meet the International Workshop on CLL (IWCLL) criteria for "active disease," which requires treatment. The initial standard therapy for most patients combines an anti-CD20 antibody (such as rituximab, ofatumumab, or obinutuzumab) with chemotherapy (fludarabine/cyclophosphamide [FC], bendamustine, or chlorambucil) depending on multiple factors including the physical fitness of the patient...
2015: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/25917267/the-phosphoinositide-3-kinase-pi3k-delta-and-gamma-inhibitor-ipi-145-duvelisib-overcomes-signals-from-the-pi3k-akt-s6-pathway-and-promotes-apoptosis-in-cll
#20
K Balakrishnan, M Peluso, M Fu, N Y Rosin, J A Burger, W G Wierda, M J Keating, K Faia, S O'Brien, J L Kutok, V Gandhi
The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0...
September 2015: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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