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https://www.readbyqxmd.com/read/28337870/jak2-tyrosine-kinase-inhibitor-ag490-suppresses-cell-growth-and-invasion-of-gallbladder-cancer-cells-via-inhibition-of-jak2-stat3-signaling
#1
L X Fu, Q W Lian, J D Pan, Z L Xu, T M Zhou, B Ye
The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) have displayed a critical role in tumor development and progression in multiple malignancies. Previous studies showed that inhibition of JAK/STAT signaling blocked cell growth and metastasis in cancer cells, however, the antitumor effects of JAK inhibitor AG490 on gallbladder cancer (GBC) have not been reported. Our present study aimed to investigate the effects and associated mechanisms of JAK inhibitor AG490 on cell growth, invasive potential and apoptosis in GBC cells (GBC-SD and SGC-996) indicated by MTT, cell colony formation, Transwell and flow cytometry...
January 2017: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/28331226/the-histone-deacetylase-inhibitor-givinostat-itf2357-exhibits-potent-anti-tumor-activity-against-crlf2-rearranged-bcp-all
#2
A M Savino, J Sarno, L Trentin, M Vieri, G Fazio, M Bardini, C Bugarin, G Fossati, K Davis, G Gaipa, S Izraeli, L H Meyer, G P Nolan, A Biondi, G Te Kronnie, C Palmi, G Cazzaniga
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert antineoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations...
March 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28330111/effect-of-stat3-inhibitor-in-chronic-myeloid-leukemia-associated-signaling-pathway-a-mathematical-modeling-simulation-and-systems-biology-study
#3
Himansu Kumar, Swapnil Tichkule, Utkarsh Raj, Saurabh Gupta, Swati Srivastava, Pritish Kumar Varadwaj
Chronic myeloid leukemia (CML) is a hematopoietic stem-cell disorder which proliferates due to abnormal growth of basophil cells. Several proangiogenic molecules have been reported to be associated in CML progression, including the hepatocyte growth factor (HGF). However, detail mechanism about the cellular distribution and function of HGF in CML is yet to be revealed. The proliferation of hematopoietic cells are regulated by some of the growth factors like interleukin 3 (IL-3), IL-6, erythropoietin, thrombopoietin, etc...
June 2016: 3 Biotech
https://www.readbyqxmd.com/read/28323260/mechanisms-and-consequences-of-jak-stat-signaling-in-the-immune-system
#4
REVIEW
Alejandro V Villarino, Yuka Kanno, John J O'Shea
Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs...
March 22, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28318222/selective-downregulation-of-jak2-and-jak3-by-an-atp-competitive-pan-jak-inhibitor
#5
S Denise Field, Jacob Arkin, Jing Li, Lyn H Jones
PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor, but it also causes selective reduction of endogenous JAK2 and JAK3 protein levels in human primary immune cells (in a time-dependent manner), leaving the other JAK family members (JAK1 and TYK2) unchanged. We found that PF-956980 selectively downregulated JAK2 and JAK3 mRNA, corresponding to changes observed at the protein level...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28301084/the-effect-of-verapamil-a-p-glycoprotein-inhibitor-on-the-pharmacokinetics-of-peficitinib-an-orally-administered-once-daily-jak-inhibitor
#6
Tong Zhu, Corrie Howieson, Tomasz Wojtkowski, Jay P Garg, David Han, Ogert Fisniku, James Keirns
Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28295194/anti-leukaemic-activity-of-the-tyk2-selective-inhibitor-ndi-031301-in-t-cell-acute-lymphoblastic-leukaemia
#7
Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R Greenwood, Hong Tiv, Takaomi Sanda, David M Weinstock, A Thomas Look
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28292965/repurposed-jak1-jak2-inhibitor-reverses-established-autoimmune-insulitis-in-non-obese-diabetic-mice
#8
Prerak M Trivedi, Kate L Graham, Nicholas A Scott, Misty R Jenkins, Suktilang Majaw, Robyn M Sutherland, Stacey Fynch, Andrew M Lew, Christopher J Burns, Balasubramanian Krishnamurthy, Thomas C Brodnicki, Stuart I Mannering, Thomas W Kay, Helen E Thomas
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics from other diseases to type 1 diabetes, especially when there is evidence for overlapping mechanisms. JAK1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and STAT1 pathway in human type 1 diabetes and in mouse models, especially in beta cells...
March 14, 2017: Diabetes
https://www.readbyqxmd.com/read/28290136/baricitinib-first-global-approval
#9
Anthony Markham
Baricitinib (Olumiant™) is an orally-administered, small-molecule, janus-associated kinase (JAK) inhibitor developed by Eli Lilly and Incyte Corporation for the treatment of rheumatoid arthritis (RA), atopic dermatitis and systemic lupus erythematosus. JAKs transduce intracellular signals from cell surface receptors for various cytokines and growth factors involved in inflammation and immune function, suggesting JAK inhibitors may be of therapeutic benefit in inflammatory conditions. In February 2017, baricitinib was approved in the EU, as monotherapy or in combination with methotrexate, for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drugs (DMARDs)...
March 13, 2017: Drugs
https://www.readbyqxmd.com/read/28289331/screening-of-breast-cancer-stem-cell-inhibitors-using-a-protein-kinase-inhibitor-library
#10
Hack Sun Choi, Dal-Ah Kim, Heesung Chung, In Ho Park, Bo Hye Kim, Eok-Soo Oh, Duk-Hee Kang
BACKGROUND: Cancer stem cells (CSCs), a subpopulation in tumors, are known to cause drug resistance, tumor recurrence and metastasis. Based on the characteristic formation of mammospheres in in vitro conditions, the mammosphere formation assay has become an essential tool for quantifying CSC activity in breast cancer research. However, manual counting of mammospheres is a time-consuming process that is not amenable to high-throughput screening, and there are occasional inaccuracies in the process of determining the mammosphere diameter...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28284718/novel-jak3-activating-mutations-in-extranodal-nk-t-cell-lymphoma-nasal-type
#11
Sung H Sim, Soyeon Kim, Tae M Kim, Yoon K Jeon, Soo J Nam, Yong-Oon Ahn, Bhumsuk Keam, Hyun H Park, Dong-Wan Kim, Chul W Kim, Dae S Heo
Inhibition of the Janus kinase (JAK)-STAT pathway has been implicated as a treatment option for extranodal natural killer/T-cell lymphoma, nasal type (NTCL). However, JAK-STAT pathway alterations in NTCL are variable, and the efficacy of JAK-STAT pathway inhibition has been poorly evaluated. JAK3 mutation and STAT3 genetic alterations were investigated by direct sequencing and immunohistochemistry in 84 patients with newly diagnosed NTCL. Five of 71 patients with NTCL (7.0%) had JAK3 mutations in the pseudokinase domain: two JAK3(A573V), two JAK3(H583Y), and one JAK3(G589D) mutation...
March 8, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28277287/the-promise-of-janus-kinase-inhibitors-in-the-treatment-of-hematological-malignancies
#12
REVIEW
Emilee Senkevitch, Scott Durum
The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas...
October 27, 2016: Cytokine
https://www.readbyqxmd.com/read/28264816/eular-recommendations-for-the-management-of-rheumatoid-arthritis-with-synthetic-and-biological-disease-modifying-antirheumatic-drugs-2016-update
#13
Josef S Smolen, Robert Landewé, Johannes Bijlsma, Gerd Burmester, Katerina Chatzidionysiou, Maxime Dougados, Jackie Nam, Sofia Ramiro, Marieke Voshaar, Ronald van Vollenhoven, Daniel Aletaha, Martin Aringer, Maarten Boers, Chris D Buckley, Frank Buttgereit, Vivian Bykerk, Mario Cardiel, Bernard Combe, Maurizio Cutolo, Yvonne van Eijk-Hustings, Paul Emery, Axel Finckh, Cem Gabay, Juan Gomez-Reino, Laure Gossec, Jacques-Eric Gottenberg, Johanna M W Hazes, Tom Huizinga, Meghna Jani, Dmitry Karateev, Marios Kouloumas, Tore Kvien, Zhanguo Li, Xavier Mariette, Iain McInnes, Eduardo Mysler, Peter Nash, Karel Pavelka, Gyula Poór, Christophe Richez, Piet van Riel, Andrea Rubbert-Roth, Kenneth Saag, Jose da Silva, Tanja Stamm, Tsutomu Takeuchi, René Westhovens, Maarten de Wit, Désirée van der Heijde
Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib)...
March 6, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28264810/promoter-methylation-modulates-indoleamine-2-3-dioxygenase-1-induction-by-activated-t-cells-in-human-breast-cancers
#14
Satish K Noonepalle, Franklin Gu, Eun-Joon Lee, Jeong-Hyeon Choi, Qimei Han, Jaejik Kim, Maria Ouzounova, Austin Y Shull, Lirong Pei, Pei-Yin Hsu, Ravindra Kohle, Fang Shi, Jiseok Choi, Katie Chiou, Tim H M Huang, Hasan Korkaya, Libin Deng, Hong-Bo Xin, Shuang Huang, Muthusamy Thangaraju, Arun Sreekumar, Stefan Ambs, Shou-Ching Tang, David H Munn, Huidong Shi
Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells...
March 6, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28260257/a-case-based-discussion-of-clinical-problems-in-the-management-of-patients-treated-with-ruxolitinib-for-myelofibrosis
#15
P Joy Ho, Ashish Bajel, Kate Burbury, Lindsay Dunlop, Simon Durrant, Cecily Forsyth, Andrew C Perkins, David M Ross
Ruxolitinib is a dual janus kinase 1 (JAK1)/JAK2 inhibitor used to treat splenomegaly and symptoms associated with myelofibrosis (MF). Current therapeutic options for symptomatic MF include supportive care, myelosuppressive therapy (such as hydroxycarbamide) and janus kinase (JAK) inhibitors (in particular ruxolitinib). Allogeneic stem cell transplantation remains the only potentially curative treatment for MF, and younger transplant-eligible patients should still be considered for allogeneic stem cell transplantation; however, this is applicable only to a small proportion of patients...
March 2017: Internal Medicine Journal
https://www.readbyqxmd.com/read/28255960/jak-stat-signaling-as-a-target-for-inflammatory-and-autoimmune-diseases-current-and-future-prospects
#16
REVIEW
Shubhasree Banerjee, Ann Biehl, Massimo Gadina, Sarfaraz Hasni, Daniella M Schwartz
The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases...
March 3, 2017: Drugs
https://www.readbyqxmd.com/read/28255337/baricitinib-in-rheumatoid-arthritis-evidence-to-date-and-clinical-potential
#17
REVIEW
Bindee Kuriya, Marc D Cohen, Ed Keystone
Biologics have changed expectation and outcomes for rheumatoid arthritis (RA). However, the optimal duration and sequence of therapy for this disease has yet to be determined. Also, a significant number of patients do not satisfactorily respond to currently available therapies. The Janus kinase (JAK) inhibitors represent a new class of therapies for RA. These drugs work uniquely by inhibiting intracellular pathways thought to be important in the pathogenesis of RA. They are available as oral agents, which is also different from the currently available biologics...
February 2017: Therapeutic Advances in Musculoskeletal Disease
https://www.readbyqxmd.com/read/28253828/emerging-protein-kinase-inhibitors-for-treating-pancreatic-cancer
#18
Junji Furuse, Fumio Nagashima
Pancreatic cancer, the incidence and mortality of which are increasing around the world, has the most dismal prognosis among the commonly encountered cancers. Systemic chemotherapy plays an important role in the treatment of patients with pancreatic cancer, and development of more effective chemotherapies is being sought. Areas covered: This review article provides a summary about protein kinase inhibitors that have been investigated for the treatment of pancreatic cancer, not only existing agents targeting RAS, EGFR, VEGFR, MEK, etc...
March 2017: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/28250461/the-emerging-safety-profile-of-jak-inhibitors-in-rheumatic-disease
#19
REVIEW
Kevin L Winthrop
Tofacitinib is the first Janus kinase (JAK) inhibitor commercially approved for the treatment of rheumatoid arthritis. This compound and a number of other JAK inhibitors are currently being tested in phase II and III trials for the treatment of a variety of autoimmune inflammatory diseases. Whereas a characteristic safety profile is emerging for some JAK inhibitors, differences between individual agents might emerge on the basis of distinct potency against their molecular targets. Similarly to biological therapy, JAK inhibition can lead to serious and opportunistic infections, and viral infections seem to be particularly frequent...
April 2017: Nature Reviews. Rheumatology
https://www.readbyqxmd.com/read/28250263/lambda-interferons-inhibit-herpes-simplex-virus-type-2-replication-in-human-cervical-epithelial-cells-through-activation-of-jak-stat-pathway
#20
Zhu Li, Xuan Lu, Yufan Zhu, Pengfei Cheng, Shi Liu, Yi Zhang, Jingfeng Tang, Sijun Yang, Li Zhou
Herpes Simplex Virus Type 2 (HSV-2) is associated with a variety of diseases, resulting in world-wide health problems. Our early study showed that lambda-interferons (IFN-λs) induced by activation of the toll-like receptors 3/ retinoic acid-inducible protein I (TLR3/RIG-I) signaling pathways contribute to inhibition of HSV-2 replication in the human cervical epithelial cells. However, anti-HSV-2 mechanisms and specific differences in signaling transduction by different IFN-λs in human cervical epithelial cells are unclear...
February 28, 2017: Japanese Journal of Infectious Diseases
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