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mtorc2 inhibitor

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https://www.readbyqxmd.com/read/29660598/first-in-human-phase-1-dose-escalation-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-dual-pi3k-and-mtorc1-2-inhibitor-pqr309-in-patients-with-advanced-solid-tumors-sakk-67-13
#1
Andreas Wicki, Nicholas Brown, Alexandros Xyrafas, Vincent Bize, Hanne Hawle, Simona Berardi, Nataša Cmiljanović, Vladimir Cmiljanović, Michael Stumm, Saša Dimitrijević, Richard Herrmann, Vincent Prêtre, Reto Ritschard, Alexandar Tzankov, Viviane Hess, Alexa Childs, Cinta Hierro, Jordi Rodon, Dagmar Hess, Markus Joerger, Roger von Moos, Cristiana Sessa, Rebecca Kristeleit
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)...
April 13, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29621478/hyperglycemia-induced-bcl-2-bax-mediated-apoptosis-of-schwann-cells-via-mtorc1-s6k1-inhibition-in-diabetic-peripheral-neuropathy
#2
Lin Zhu, Jun Hao, Meijuan Cheng, Cuihong Zhang, Chunxiu Huo, Yaping Liu, Wei Du, Xianghong Zhang
Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques...
April 2, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29617677/the-mtor-kinase-inhibitor-cz415-inhibits-human-papillary-thyroid-carcinoma-cell-growth
#3
Xiaobin Li, Zongze Li, Yimin Song, Wenjing Liu, Ziwen Liu
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. METHODS: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively...
March 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29571732/induction-of-mek-erk-activity-by-azd8055-confers-acquired-resistance-in-neuroblastoma
#4
Dong-Qing Xu, Hidemi Toyoda, Lei Qi, Mari Morimoto, Ryo Hanaki, Shotaro Iwamoto, Yoshihiro Komada, Masahiro Hirayama
Mammalian target of rapamycin (mTOR) complex (mTORC) is frequently activated in diverse cancers. Although dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. AZD8055 is a novel, potent ATP-competitive and specific inhibitor of mTOR kinase activity, which blocks both mTORC1 and mTORC2 activation. In this study, we acquired AZD8055-resistant neuroblastoma (NB) cell sublines by using prolonged stepwise escalation of AZD8055 exposure (4-12 weeks)...
March 20, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29535262/skp2-dependent-reactivation-of-akt-drives-resistance-to-pi3k-inhibitors
#5
Emilie Clement, Hiroyuki Inuzuka, Naoe T Nihira, Wenyi Wei, Alex Toker
The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of PIK3CA occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways...
March 13, 2018: Science Signaling
https://www.readbyqxmd.com/read/29523752/drug-discovery-targeting-the-mtor-pathway
#6
REVIEW
Alberto M Martelli, Francesca Buontempo, James A McCubrey
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential...
March 15, 2018: Clinical Science (1979-)
https://www.readbyqxmd.com/read/29518209/a-germline-specific-role-for-the-mtorc2-component-rictor-in-maintaining-spermatogonial-differentiation-and-intercellular-adhesion-in-mouse-testis
#7
Shun Bai, Le Cheng, Yingwen Zhang, Chunsen Zhu, Zhiping Zhu, Ruping Zhu, C Yan Cheng, Lan Ye, Ke Zheng
STUDY QUESTION: What is the physiological role of Rictor in spermatogenic cells? SUMMARY ANSWER: Germline expression of Rictor regulates spermatogonial differentiation and has an essential role in coordinating germ cells and Sertoli cells in maintaining intact cell-cell adhesion dynamics and cytoskeleton-based architecture in the seminiferous epithelium. WHAT IS KNOWN ALREADY: The mechanistic target of rapamycin (mTOR) resides in its functions as the catalytic subunits of the structurally and functionally distinct mTORC1 and mTORC2 complexes...
February 6, 2018: Molecular Human Reproduction
https://www.readbyqxmd.com/read/29506143/mtor-pathway-is-activated-in-endothelial-cells-from-patients-with-takayasu-arteritis-and-is-modulated-by-serum-immunoglobulin-g
#8
Jérôme Hadjadj, Guillaume Canaud, Tristan Mirault, Maxime Samson, Patrick Bruneval, Alexis Régent, Claire Goulvestre, Véronique Witko-Sarsat, Nathalie Costedoat-Chalumeau, Loïc Guillevin, Luc Mouthon, Benjamin Terrier
Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA...
February 27, 2018: Rheumatology
https://www.readbyqxmd.com/read/29499203/anti-tumor-effect-of-azd8055-against-neuroblastoma-cells-in-vitro-and-in-vivo
#9
Dong-Qing Xu, Hidemi Toyoda, Xiao-Jun Yuan, Lei Qi, Vipin Shankar Chelakkot, Mari Morimoto, Ryo Hanaki, Kentarou Kihira, Hiroki Hori, Yoshihiro Komada, Masahiro Hirayama
Neuroblastoma (NB) is one of the most common solid tumors in children. High-risk NB remains lethal in about 50% of patients despite comprehensive and intensive treatments. Activation of PI3K/Akt/mTOR signaling pathway correlates with oncogenesis, poor prognosis and chemotherapy resistance in NB. Due to its central role in growth and metabolism, mTOR seems to be an important factor in NB, making it a possible target for NB. In this study, we investigated the effect of AZD8055, a potent dual mTORC1-mTORC2 inhibitor, in NB cell lines...
February 27, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29491070/azd8055-exerts-antitumor-effects-on-colon-cancer-cells-by-inhibiting-mtor-and-cell-cycle-progression
#10
Yun Chen, Cheng-Hung Lee, Bor-Yuan Tseng, Ya-Hui Tsai, Huang-Wen Tsai, Chao-Ling Yao, Sheng-Hong Tseng
BACKGROUND/AIM: AZD8055 is an inhibitor of mammalian target of rapamycin (mTOR) that can suppress both mTOR complex 1 (mTORC1) and mTORC2. This study investigated the antitumor effects of AZD8055 on colon cancer. MATERIALS AND METHODS: The effects of AZD8055 on proliferation, apoptosis, and cell cycle of colon cancer cells, and tumor growth in a mouse colon cancer model were studied. RESULTS: AZD8055 significantly inhibited proliferation and induced apoptosis of colon cancer cells (p<0...
March 2018: Anticancer Research
https://www.readbyqxmd.com/read/29487597/loss-of-rictor-in-monocyte-macrophages-suppresses-their-proliferation-and-viability-reducing-atherosclerosis-in-ldlr-null-mice
#11
Vladimir R Babaev, Jiansheng Huang, Lei Ding, Youmin Zhang, James M May, MacRae F Linton
Background: Rictor is an essential component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2), a conserved serine/threonine kinase that may play a role in cell proliferation, survival and innate or adaptive immune responses. Genetic loss of Rictor inactivates mTORC2, which directly activates Akt S473 phosphorylation and promotes pro-survival cell signaling and proliferation. Methods and results: To study the role of mTORC2 signaling in monocytes and macrophages, we generated mice with myeloid lineage-specific Rictor deletion (M Rictor -/- )...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29481864/depdc5-and-nprl3-modulate-cell-size-filopodial-outgrowth-and-localization-of-mtor-in-neural-progenitor-cells-and-neurons
#12
Philip H Iffland, Marianna Baybis, Allan E Barnes, Richard J Leventer, Paul J Lockhart, Peter B Crino
Mutations in DEPDC5 and NPRL3 subunits of GATOR1, a modulator of mechanistic target of rapamycin (mTOR), are linked to malformations of cortical development (MCD). Brain specimens from these individuals reveal abnormal cortical lamination, altered cell morphology, and hyperphosphorylation of ribosomal S6 protein (PS6), a marker for mTOR activation. While numerous studies have examined GATOR1 subunit function in non-neuronal cell lines, few have directly assessed loss of GATOR 1 subunit function in neuronal cell types...
February 23, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29475988/hla-class-ii-triggered-signaling-cascades-cause-endothelial-cell-proliferation-and-migration-relevance-to-antibody-mediated-transplant-rejection
#13
Yi-Ping Jin, Nicole M Valenzuela, Xiaohai Zhang, Enrique Rozengurt, Elaine F Reed
Transplant recipients developing donor-specific HLA class II (HLA-II) Abs are at higher risk for Ab-mediated rejection (AMR) and transplant vasculopathy. To understand how HLA-II Abs cause AMR and transplant vasculopathy, we determined the signaling events triggered in vascular endothelial cells (EC) following Ab ligation of HLA-II molecules. HLA-II expression in EC was induced by adenoviral vector expression of CIITA or by pretreatment with TNF-α/IFN-γ. Ab ligation of class II stimulated EC proliferation and migration...
February 23, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29434241/streptomyces-sp-metabolite-s-promotes-bax-mediated-intrinsic-apoptosis-and-autophagy-involving-inhibition-of-mtor-pathway-in-cervical-cancer-cell-lines
#14
Vipin Mohan Dan, Balaji Muralikrishnan, Rahul Sanawar, Vinodh J S, Bhushan Bapusaheb Burkul, Kalanghad Puthankalam Srinivas, Asha Lekshmi, N S Pradeep, Syed G Dastager, B Santhakumari, Thankayyan R Santhoshkumar, R Ajay Kumar, Madhavan Radhakrishna Pillai
In cervical cancer, the association between HPV infection and dysregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR pathway) places mTOR as an attractive therapeutic target. The failure of current treatment modalities in advanced stages of this cancer and drawbacks of already available mTOR inhibitors demand for novel drug candidates. In the present study we identified the presence of a mTOR inhibitor in an active fraction of the ethyl acetate extract of Streptomyces sp OA293...
February 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29432734/the-anti-osteosarcoma-cell-activity-by-a-mtorc1-2-dual-inhibitor-res-529
#15
Xujun Hu, Zirui Wang, Meikai Chen, Xuerong Chen, Wenqing Liang
mTOR over-activation is important for human osteosarcoma (OS) tumorigenesis and progression. RES-529 is a mTORC1/2 dual inhibitor. Here, our results show that RES-529 inhibited viability, cell cycle progression and proliferation of the established (U2OS line) and primary human OS cells. RES-529 induced apoptosis activation in OS cells. It was yet non-cytotoxic to OB-6 osteoblastic cells and the primary human osteoblasts. RES-529 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-mLST8 association) in human OS cells, blocking mTORC1/2 activation...
February 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29428724/dual-inhibition-of-mtorc1-and-mtorc2-perturbs-cytoskeletal-organization-and-impairs-endothelial-cell-elongation
#16
Kiyomi Tsuji-Tamura, Minetaro Ogawa
Elongation of endothelial cells is an important process in vascular formation and is expected to be a therapeutic target for inhibiting tumor angiogenesis. We have previously demonstrated that inhibition of mTORC1 and mTORC2 impaired endothelial cell elongation, although the mechanism has not been well defined. In this study, we analyzed the effects of the mTORC1-specific inhibitor everolimus and the mTORC1/mTORC2 dual inhibitor KU0063794 on the cytoskeletal organization and morphology of endothelial cell lines...
February 8, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29416044/a-small-molecule-inhibitor-of-rheb-selectively-targets-mtorc1-signaling
#17
Sarah J Mahoney, Sridhar Narayan, Lisa Molz, Lauren A Berstler, Seong A Kang, George P Vlasuk, Eddine Saiah
The small G-protein Rheb activates the mechanistic target of rapamycin complex 1 (mTORC1) in response to growth factor signals. mTORC1 is a master regulator of cellular growth and metabolism; aberrant mTORC1 signaling is associated with fibrotic, metabolic, and neurodegenerative diseases, cancers, and rare disorders. Point mutations in the Rheb switch II domain impair its ability to activate mTORC1. Here, we report the discovery of a small molecule (NR1) that binds Rheb in the switch II domain and selectively blocks mTORC1 signaling...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29408410/the-role-of-mtor-mediated-signaling-in-the-regulation-of-cellular-migration
#18
REVIEW
Ailsa K Holroyd, Alison M Michie
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration...
February 3, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29402408/cc-223-inhibits-human-head-and-neck-squamous-cell-carcinoma-cell-growth
#19
Jun-Ying Wang, Xin Jin, Xin Zhang, Xiao-Feng Li
mTOR over-activation is associated with the progression of head and neck squamous cell carcinoma (HNSCC). CC-223 is a novel and potent mTOR kinase inhibitor. Its activity against human HNSCC cells is studied here. In established SCC-9 cells and primary human oral cavity carcinoma (OCC) cells, CC-223 treatment at only nM concentrations significantly inhibited survival, proliferation and cell cycle progression. Furthermore, CC-223 provoked apoptosis activation in human HNSCC cells. CC-223 is more efficient in killing HNSCC cells than other known Akt-mTOR inhibitors: RAD001, MK-2206 and AZD-2014...
January 31, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29384525/mtor-inhibitor-based-combination-therapies-for-pancreatic-cancer
#20
Zonera Hassan, Christian Schneeweis, Matthias Wirth, Christian Veltkamp, Zahra Dantes, Benedikt Feuerecker, Güralp O Ceyhan, Shirley K Knauer, Wilko Weichert, Roland M Schmid, Roland Stauber, Alexander Arlt, Oliver H Krämer, Roland Rad, Maximilian Reichert, Dieter Saur, Günter Schneider
BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance...
February 6, 2018: British Journal of Cancer
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