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https://www.readbyqxmd.com/read/28350788/ldl-cholesterol-counteracts-the-antitumour-effect-of-tyrosine-kinase-inhibitors-against-renal-cell-carcinoma
#1
Sei Naito, Peter Makhov, Igor Astsaturov, Konstantin Golovine, Alexei Tulin, Alexander Kutikov, Robert G Uzzo, Vladimir M Kolenko
BACKGROUND: Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. METHODS: We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib...
March 28, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28346741/small-molecules-targeting-human-n-acetylmannosamine-kinase
#2
Stephan Hinderlich, Martin Neuenschwander, Paul-Robin Wratil, Andreas Oder, Michael Lisurek, Long D Nguyen, Jens Peter von Kries, Christian Hackenberger
N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. For the search of effective inhibitors of MNK we applied high-throughput screening of drug-like small molecules. Applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50 values in the low micromolar range...
March 27, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28346673/clinical-features-of-bim-deletion-polymorphism-and-its-relation-with-crizotinib-primary-resistance-in-chinese-patients-with-alk-ros1-fusion-positive-non-small-cell-lung-cancer
#3
Limin Zhang, Tao Jiang, Xuefei Li, Yan Wang, Chao Zhao, Sha Zhao, Lei Xi, Shijia Zhang, Xiaozhen Liu, Yijun Jia, Hui Yang, Jinpeng Shi, Chunxia Su, Shengxiang Ren, Caicun Zhou
BACKGROUND: The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib...
March 27, 2017: Cancer
https://www.readbyqxmd.com/read/28346439/hippo-signalling-governs-cytosolic-nucleic-acid-sensing-through-yap-taz-mediated-tbk1-blockade
#4
Qian Zhang, Fansen Meng, Shasha Chen, Steven W Plouffe, Shiying Wu, Shengduo Liu, Xinran Li, Ruyuan Zhou, Junxian Wang, Bin Zhao, Jianming Liu, Jun Qin, Jian Zou, Xin-Hua Feng, Kun-Liang Guan, Pinglong Xu
The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates...
March 27, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28346237/current-and-future-pharmacologic-treatment-of-nonalcoholic-steatohepatitis
#5
Bubu A Banini, Arun J Sanyal
PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), can progress to cirrhosis and hepatocellular cancer in 5-15% of patients and is rapidly becoming the leading cause for end-stage liver disease. Dietary caloric restriction and exercise, currently the cornerstone of therapy for NAFLD, can be difficult to achieve and maintain, underscoring the dire need for pharmacotherapy. This review presents the agents currently used in managing NAFLD and their pharmacologic targets...
March 24, 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28346107/a-high-throughput-method-for-measuring-drug-residence-time-using-the-transcreener-adp-assay
#6
Meera Kumar, Robert G Lowery
Analysis of drug-target residence times during drug development can result in improved efficacy, increased therapeutic window, and reduced side effects. Residence time can be estimated as the reciprocal of the dissociation rate ( koff) of an inhibitor from its target. The traditional methods for measuring koff require synthesis of labeled ligands or low-throughput label-free methods. To provide an alternative that is better suited to an automated high-throughput screening (HTS) environment, we adapted a classic "jump dilution" catalytic assay method for determination of koff values for kinase inhibitor drugs...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28346103/discovery-of-novel-gq-biased-lpa1-negative-allosteric-modulators
#7
Yuji Shimizu, Masaharu Nakayama
Lysophosphatidic acid (LPA) activates the G-protein-coupled receptor LPA1, which regulates various cellular processes, including cell proliferation and migration. Although LPA1 transduces cellular responses via Gq, Gi, and G12/13, associations between these signaling molecules and cellular phenotypes remain poorly characterized due to the lack of signal-specific pharmacological tools. Here, we characterized novel signal-biased modulators using multiple assays, including label-free impedance assays. LPA caused dramatic changes in cellular impedance in LPA1-expressing recombinant cells, which were susceptible to G-protein and protein kinase inhibitors...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28345463/computational-and-mechanistic-studies-on-the-effect-of-galactoxyloglucan-imatinib-nanoconjugate-in-imatinib-resistant-k562-cells
#8
Alphy Rose James, B S Unnikrishnan, R Priya, Manu M Joseph, T K Manojkumar, K Raveendran Pillai, R Shiji, G U Preethi, P Kusumakumary, T T Sreelekha
Imatinib mesylate, a BCR/ABL fusion protein inhibitor, is the first-line treatment against chronic myelogenous leukemia. In spite of its advantageous viewpoints, imatinib still has genuine impediments like undesirable side effects and tumor resistance during chemotherapy. Nanoparticles with sustainable release profile will help in targeted delivery of anticancer drugs while minimizing deleterious side effects and drug resistance. The use of biopolymers like galactoxyloglucan (PST001) for the fabrication of imatinib mesylate nanoparticles could impart its use in overcoming multidrug resistance in chronic myelogenous leukemia patients with minimal side effects...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28344857/metastatic-braf-k601e-mutated-melanoma-reaches-complete-response-to-mek-inhibitor-trametinib-administered-for-over-36%C3%A2-months
#9
Riccardo Marconcini, Luca Galli, Andrea Antonuzzo, Simona Bursi, Claudia Roncella, Gabriella Fontanini, Elisa Sensi, Alfredo Falcone
BACKGROUND: The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs. CASE PRESENTATION: A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28344765/new-insights-on-thyroid-hormone-mediated-regulation-of-herpesvirus-infections
#10
REVIEW
Robert W Figliozzi, Feng Chen, S Victor Hsia
Thyroid hormone (T3) has been suggested to participate in the regulation of herpesvirus replication during reactivation. Clinical observations and in vivo experiments suggest that T3 are involved in the suppression of herpes virus replication. In vitro, differentiated LNCaP cells, a human neuron-like cells, further resisted HSV-1 replication upon addition of T3. Previous studies indicate that T3 controlled the expression of several key viral genes via its nuclear receptors in differentiated LNCaP cells. Additional observation showed that differentiated LNCaP cells have active PI3K signaling and inhibitor LY294002 can reverse T3-mediated repression of viral replication...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28344665/treatment-choice-in-epidermal-growth-factor-receptor-mutation-positive-non-small-cell-lung-carcinoma-latest-evidence-and-clinical-implications
#11
REVIEW
Oscar Juan, Sanjay Popat
Discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the subsequent development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the treatment of lung cancer. First-line treatment with EGFR TKIs (gefitinib, erlotinib and afatinib) has demonstrated a superior response rate and progression-free survival (PFS) compared with chemotherapy in EGFR-mutation positive patients. However, a number of open questions remain, such as choice between the three EGFR TKIs licensed, treatment of patients unsuitable for chemotherapy due to morbidity or advanced age, management of acquired resistance and optimal biological sample to determine EGFR status...
March 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28344175/transforming-growth-factor-%C3%AE-family-in-the-pathogenesis-of-meningiomas
#12
REVIEW
Mahlon D Johnson
OBJECTIVES: Meningiomas represent thirty-six percent of primary brain tumors. The pathogenesis of these tumors is not completely established hindering development of effective chemotherapy. Recently, numerous studies have identified alterations in several growth factors/receptor kinases that regulate meningioma growth. These may be targets for new therapies. . Of these and, sometimes overlooked, is the TGF-β family, its receptors and signaling pathways plays a critical role in the development or progression of many forms of neoplasia...
March 23, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28344171/lipopolysaccharide-induced-interleukin-6-production-is-mediated-through-activation-of-erk-1-2-p38-mapk-mek-and-nf%C3%AE%C2%BAb-in-chicken-thrombocytes
#13
C Winkler, F Ferdous, M Dimmick, T Scott
Thrombocytes express Toll-like receptor 4 and apparently use both mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB) pathways for nuclear signaling. However, it is not well known if the same enzyme systems found in mammalian cells are fully functional in chickens. Therefore, kinase inhibitors were used with thrombocytes to block kinases in lipopolysaccharide (LPS) stimulated cells to determine if interleukin (IL)-6 expression and production would be diminished...
March 23, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28343377/protein-kinase-c-mediates-the-corticosterone-induced-sensitization-of-dorsal-root-ganglion-neurons-innervating-the-rat-stomach
#14
Meng Li, Lu Xue, Hong-Yan Zhu, Hongjun Wang, Xue Xu, Geping Wu, Guang-Yin Xu
Background/Aims: Gastric hypersensitivity contributes to abdominal pain in patients with functional dyspepsia (FD). Recent studies showed that hormones induced by stress are correlated with visceral hypersensitivity. However, the precise mechanisms underlying gastric hypersensitivity remain largely unknown. The aim of the present study was designed to investigate the roles of corticosterone (CORT) on excitability of dorsal root ganglion (DRG) neurons innervating the stomach. Methods: DRG neurons innervating the stomach were labeled by DiI injection into the stomach wall...
March 26, 2017: Journal of Neurogastroenterology and Motility
https://www.readbyqxmd.com/read/28343336/sunitinib-induced-hypothyroidism-predicts-progression-free-survival-in-metastatic-renal-cell-carcinoma-patients
#15
Anna Buda-Nowak, Jakub Kucharz, Paulina Dumnicka, Marek Kuzniewski, Roman Maria Herman, Aneta L Zygulska, Beata Kusnierz-Cabala
Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib...
April 2017: Medical Oncology
https://www.readbyqxmd.com/read/28343126/pi3k-signaling-in-cancer-beyond-akt
#16
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/28342996/induction-of-neuroendocrine-differentiation-in-prostate-cancer-cells-by-dovitinib-tki-258-and-its-therapeutic-implications
#17
Shalini S Yadav, Jinyi Li, Jennifer A Stockert, Bryan Herzog, James O'Connor, Luis Garzon-Manco, Ramon Parsons, Ashutosh K Tewari, Kamlesh K Yadav
Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC...
March 24, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28342896/neuroprotective-and-axonal-outgrowth-promoting-effects-of-tetramethylpyrazine-nitrone-in-chronic-cerebral-hypoperfusion-rats-and-primary-hippocampal-neurons-exposed-to-hypoxia
#18
Tao Zhang, Jianbo Gu, Liangmiao Wu, Ning Li, Yewei Sun, Pei Yu, Yuqiang Wang, Gaoxiao Zhang, Zaijun Zhang
Chronic cerebral hypoperfusion is an important risk factor for vascular dementia and other brain dysfunctions, for which there are currently no effective medications available. We investigated the neuroprotective and axonal outgrowth promoting effects of tetramethylpyrazine nitrone (TBN) in a permanent bilateral occlusion of the common carotid arteries (2VO) rat model and in primary hippocampal neurons exposed to oxygen glucose deprivation (OGD). At 6th week after 2VO, TBN increased the time spent in novel arms in the Y-maze test and improved the discrimination ratio in object reorganization task...
March 22, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28342850/structural-basis-for-differential-activities-of-enantiomeric-ppar%C3%AE-agonists-binding-of-s35-to-the-alternate-site
#19
Jun Young Jang, Minseob Koh, Hwan Bae, Doo Ri An, Ha Na Im, Hyoun Sook Kim, Ji Young Yoon, Hye-Jin Yoon, Byung Woo Han, Seung Bum Park, Se Won Suh
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARγ agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) of the ligand-binding domain (LBD). More recently, an alternate ligand-binding site was identified in PPARγ LBD; it is located beside the Ω loop between the helices H2' and H3...
March 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28342808/role-of-mtorc1-s6k1-signaling-pathway-in-regulation-of-hematopoietic-stem-cell-and-acute-myeloid-leukemia
#20
REVIEW
Joydeep Ghosh, Reuben Kapur
Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions...
March 22, 2017: Experimental Hematology
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