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Mek inhibitor

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https://www.readbyqxmd.com/read/29775310/fragment-based-discovery-of-a-potent-orally-bioavailable-inhibitor-which-modulates-the-phosphorylation-and-catalytic-activity-of-erk1-2
#1
Tom D Heightman, Valerio Berdini, Hannah Braithwaite, Ildiko Maria Buck, Megan Cassidy, Juan Castro, Aurelie Courtin, James E H Day, Charlotte East, Lynsey Fazal, Brent Graham, Charlotte M Griffiths-Jones, John F Lyons, Vanessa Martins, Sandra Muench, Joanne M Munck, David Norton, Marc O'Reilly, Nick Palmer, Puja Pathuri, Michael Reader, David C Rees, Sharna J Rich, Caroline Richardson, Harpreet Saini, Neil T Thompson, Nicola G Wallis, Hugh Walton, Nicola E Wilsher, Alison J-A Woolford, Michael Cooke, David Cousin, Stuart Onions, Jonathan Shannon, John Watts, Christopher W Murray
Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity...
May 18, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29774100/differential-proteomic-profile-of-leukemic-cd34-progenitor-cells-from-chronic-myeloid-leukemia-patients
#2
Maria Rosaria Ricciardi, Valentina Salvestrini, Roberto Licchetta, Simone Mirabilii, Mattia Forcato, Gabriele Gugliotta, Simona Salati, Fausto Castagnetti, Gianantonio Rosti, Massimo Breccia, Giuliana Alimena, Rossella Manfredini, Silvio Bicciato, Roberto Massimo Lemoli, Agostino Tafuri
Chronic Myeloid Leukemia (CML) is a stem cell disease sustained by a rare population of quiescent cells which are to some extent resistant to tyrosine kinase inhibitors (TKIs). BCR-ABL oncogene activates multiple cross-talking signal transduction pathways (STP), such as RAS/MEK/ERK, PI3K/Akt, Wnt and STAT5, contributing to abnormal proliferation of clonal cells. From this perspective, the aim of this study was to analyze the expression and activation profile of STP involved in the mechanisms of cell proliferation/quiescence and survival of the progenitor CD34+ cells from chronic phase (CP) CML...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29774094/selumetinib-based-therapy-in-uveal-melanoma-patient-derived-xenografts
#3
Didier Decaudin, Rania El Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Chloé Raymondie, Emma Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul D Smith, Nathalie Cassoux, Sophie Piperno-Neumann, Sergio Roman-Roman, Fariba Némati
The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29768711/clinical-resistance-associated-with-a-novel-map2k1-mutation-in-a-patient-with-langerhans-cell-histiocytosis
#4
David O Azorsa, David W Lee, Daniel H Wai, Ranjan Bista, Apurvi R Patel, Eiman Aleem, Michael M Henry, Robert J Arceci
Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p...
May 16, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#5
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29767261/inhibition-of-mek-erk-stat3-signaling-in-oleuropein-treatment-inhibits-myocardial-ischemia-reperfusion
#6
Hong-Xu Jin, Yun-Hu Zhang, Ruo-Nan Guo, Su-Nuan Zhao
Studies have shown that oleuropein has antifungal, anti‑inflammatory, antiviral, antioxidant, anticancer and hypoglycemic functions. TTC solution staining was used to measure myocardial infarction size. A commercial kit was used to measure lactate dehydrogenase (LDH), creatinine kinase‑MB (CK‑MB), tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), IL 6, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase levels. Western blot analysis was used to measure p53, p-MEK p-ERK and p‑IκBα protein expression...
May 11, 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29766299/molecularly-defined-diffuse-leptomeningeal-glioneuronal-tumor-dlgnt-comprises-two-subgroups-with-distinct-clinical-and-genetic-features
#7
Maximilian Y Deng, Martin Sill, Jason Chiang, Jens Schittenhelm, Martin Ebinger, Martin U Schuhmann, Camelia-Maria Monoranu, Till Milde, Andrea Wittmann, Christian Hartmann, Clemens Sommer, Werner Paulus, Jutta Gärtner, Wolfgang Brück, Thomas Rüdiger, Alfred Leipold, Zane Jaunmuktane, Sebastian Brandner, Felice Giangaspero, Paolo Nozza, Jaume Mora, Andres Morales la Madrid, Ofelia Cruz Martinez, Jordan R Hansford, Torsten Pietsch, Anna Tietze, Pablo Hernáiz-Driever, Iris Stoler, David Capper, Andrey Korshunov, David W Ellison, Andreas von Deimling, Stefan M Pfister, Felix Sahm, David T W Jones
Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs...
May 15, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29763915/serum-from-chronic-hepatitis-b-patients-promotes-growth-and-proliferation-via-the-igf-ii-igf-ir-mek-erk-signaling-pathway-in-hepatocellular-carcinoma-cells
#8
Yuanyuan Ji, Zhidong Wang, Haiyan Chen, Lei Zhang, Fei Zhuo, Qingqing Yang
BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. METHODS: Levels of circulating IGF-II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA...
May 9, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29763460/lipophilic-statins-limit-cancer-cell-growth-and-survival-via-involvement-of-akt-signaling
#9
Colin H Beckwitt, Keisuke Shiraha, Alan Wells
The HMG-CoA reductase inhibitors, statins, have been used as lipid lowering drugs for decades and several epidemiological studies suggest statin usage correlates with a decreased incidence of cancer specific mortality in patients. However, the mechanism of this mortality benefit remains unclear. Here, we demonstrate that statin drug lipophilicity and affinity for its target enzyme, HMGCR, determine their growth suppressive potency against various tumor cell lines. The lipophilic atorvastatin decreases cancer cell proliferation and survival in vitro...
2018: PloS One
https://www.readbyqxmd.com/read/29760222/erk-mutations-and-amplification-confer-resistance-to-erk-inhibitor-therapy
#10
Bijay S Jaiswal, Steffen Durinck, Eric Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John G Moffat, Scott Martin, Zora Modrusan, Somasekar Seshagiri
PURPOSE: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF and/or RAS mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance...
May 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29760048/tipifarnib-inhibits-hras-driven-dedifferentiated-thyroid-cancers
#11
Brian R Untch, Vanessa Dos Anjos, Maria E R Garcia-Rendueles, Jeffrey A Knauf, Gnana P Krishnamoorthy, Mahesh Saqcena, Umeshkumar K Bhanot, Nicholas D Socci, Alan L Ho, Ronald Ghossein, James A Fagin
Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS-MAPK signaling was abrogated in vitro by selective RTK (i...
May 14, 2018: Cancer Research
https://www.readbyqxmd.com/read/29757973/a-new-strategy-to-control-and-eradicate-undruggable-oncogenic-k-ras-driven-pancreatic-cancer-molecular-insights-and-core-principles-learned-from-developmental-and-evolutionary-biology
#12
REVIEW
Robert E Van Sciver, Michael P Lee, Caroline Dasom Lee, Alex C Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L Colliver, Lauren L Siewertsz van Reesema, Angela M Tang-Tan, Vasilena Zheleva, Monicah N Bwayi, Minglei Bian, Rebecca L Schmidt, Lynn M Matrisian, Gloria M Petersen, Amy H Tang
Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH)...
May 14, 2018: Cancers
https://www.readbyqxmd.com/read/29755294/inhibition-of-the-pi3k-but-not-the-mek-erk-pathway-sensitizes-human-glioma-cells-to-alkylating-drugs
#13
Bodo Haas, Veronika Klinger, Christina Keksel, Verena Bonigut, Daniela Kiefer, Julia Caspers, Julia Walther, Maria Wos-Maganga, Sandra Weickhardt, Gabriele Röhn, Marco Timmer, Roland Frötschl, Niels Eckstein
Background: Intrinsic chemoresistance of glioblastoma (GBM) is frequently owed to activation of the PI3K and MEK/ERK pathways. These signaling cascades are tightly interconnected however the quantitative contribution of both to intrinsic resistance is still not clear. Here, we aimed at determining the activation status of these pathways in human GBM biopsies and cells and investigating the quantitative impact of both pathways to chemoresistance. Methods: Receptor tyrosine kinase (RTK) pathways in temozolomide (TMZ) treatment naive or TMZ resistant human GBM biopsies and GBM cells were investigated by proteome profiling and immunoblotting of a subset of proteins...
2018: Cancer Cell International
https://www.readbyqxmd.com/read/29754815/an-acquired-vulnerability-of-drug-resistant-melanoma-with-therapeutic-potential
#14
Liqin Wang, Rodrigo Leite de Oliveira, Sanne Huijberts, Evert Bosdriesz, Nora Pencheva, Diede Brunen, Astrid Bosma, Ji-Ying Song, John Zevenhoven, G Tjitske Los-de Vries, Hugo Horlings, Bastiaan Nuijen, Jos H Beijnen, Jan H M Schellens, Rene Bernards
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells...
April 28, 2018: Cell
https://www.readbyqxmd.com/read/29753091/increase-in-constitutively-active-mek1-species-by-introduction-of-mek1-mutations-identified-in-cancers
#15
Emiko Kinoshita-Kikuta, Eiji Kinoshita, Sayaka Ueda, Yoko Ino, Yayoi Kimura, Hisashi Hirano, Tohru Koike
The kinase MEK1 is an essential component of the mitogen-activated protein kinase cascades. Somatic mutations that have been identified in the MEK1-coding gene generally enhance kinase activity. Consequently, MEK1 has attracted much interest as a target for cancer therapy to block the aberrant activity. By using Phos-tag affinity electrophoresis, we found that the introduction of mutations detected in certain sporadic cancers or in MEK-inhibitor-resistant cancer cells produced constitutively active MEK1 species containing phosphorylated Ser-218 and Ser-222 residues; it also enhanced the constitutive activity of the kinase...
May 9, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29750425/increased-infiltration-of-macrophages-to-radioresistant-lung-cancer-cells-contributes-to-the-development-of-the-additional-resistance-of-tumor-cells-to-the-cytotoxic-effects-of-nk-cells
#16
Mingjing Shen, Yongbing Chen, Lijun Xu, Rongying Zhu, Xiang Xue, Ying Tsai, Peter C Keng, Soo Ok Lee, Yuhchyau Chen
In this study, in order to investigate the effects of increased macrophage infiltration to radioresistant lung tumors in regulating natural killer (NK) cell-mediated immunity, we examined whether the treatment of radioresistant cells with conditioned medium (CM) from phorbol myristate acetate (PMA)/interleukin (IL)-4 treated THP-1 cells (used as a tumor-associated macrophage source) leads to the development of the additional resistance of tumor cells to NK cell cytotoxicity. We found that the susceptibility of THP-1 CM-treated radioresistant cells to NK cell cytotoxicity was decreased compared to the non-treated cells...
May 4, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29749533/egf-upregulates-rfpl3-and-htert-via-the-mek-signaling-pathway-in-non%C3%A2-small-cell-lung-cancer-cells
#17
Chuan Lin, Yu Qin, Hua Zhang, Ming-Yang Gao, Yan-Fu Wang
Activation of the epidermal growth factor receptor (EGFR) during tumor development can trigger the MEK signaling pathway. In the present study, we investigated the MEK signaling pathway in non‑small cell lung cancer (NSCLC) cells with respect to the effect of epidermal growth factor (EGF) on expression of Ret finger protein like 3 (RFPL3) and human telomerase reverse transcriptase (hTERT), and the effect of RFPL3 overexpression on other MEK signaling proteins. In vitro, A549 and H1299 cells were treated with different concentrations of EGF for 24 h or 48 h...
May 8, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29747484/prolonged-survival-of-a-patient-with-brain-melanoma-metastasis-treated-with-braf-and-mek-inhibitors-combination-therapy
#18
Giulia Spallone, Virginia Garofalo, Eliseo Picchi, Rossella Pitocco, Federico Bianchi, Alessandra Ventura, Riccardo Santoni, Luca Bianchi
No abstract text is available yet for this article.
May 10, 2018: Giornale Italiano di Dermatologia e Venereologia: Organo Ufficiale, Società Italiana di Dermatologia e Sifilografia
https://www.readbyqxmd.com/read/29742974/neoadjuvant-braf-and-immune-directed-therapy-for-anaplastic-thyroid-carcinoma
#19
Maria Cabanillas, Renata Ferrarotto, Adam Garden, Salmaan Ahmed, Naifa Busaidy, Ramona Dadu, Michelle D Williams, Heath Skinner, Brandon Gunn, Horiana Grosu, Priyanka C Iyer, Marie-Claude Hofmann, Mark Zafereo
Anaplastic thyroid cancer (ATC) is a devastating disease with a dismal prognosis. Patients who have disease confined to the thyroid and who are able to undergo complete surgery and chemoradiation stand the best chance for survival. Unfortunately, nearly 50% of patients at diagnosis have distant metastases at diagnosis and most present with locally advanced, unresectable tumors. Nevertheless, BRAF-mutated ATC patients represent a subset of cases who can benefit from a combination therapy with BRAF and /MEK inhibitors...
May 10, 2018: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/29740790/identification-of-inhibitors-synergizing-gemcitabine-sensitivity-in-the-squamous-subtype-of-pancreatic-ductal-adenocarcinoma-pdac
#20
Jia Lin Er, Pei Ni Goh, Chen Yuan Lee, Ying Jie Tan, Ling-Wei Hii, Chun Wai Mai, Felicia Fei-Lei Chung, Chee-Onn Leong
Pancreatic adenocarcinoma (PDAC) is a highly aggressive cancer with a high chance of recurrence, limited treatment options, and poor prognosis. A recent study has classified pancreatic cancers into four molecular subtypes: (1) squamous, (2) immunogenic, (3) pancreatic progenitor and (4) aberrantly differentiated endocrine exocrine. Among all the subtypes, the squamous subtype has the worst prognosis. This study aims to utilize large scale genomic datasets and computational systems biology to identify potential drugs targeting the squamous subtype of PDAC through combination therapy...
May 8, 2018: Apoptosis: An International Journal on Programmed Cell Death
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