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https://www.readbyqxmd.com/read/28645859/discovery-of-a-novel-pan-raf-inhibitor-with-potent-anti-tumor-activity-in-preclinical-models-of-braf-v600e-mutant-cancer
#1
Sung Pyo Hong, Soon Kil Ahn
AIMS: BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF-mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan-RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations...
June 20, 2017: Life Sciences
https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#2
Zhaobo Li, Lihong Zhou, Chrisostomos Prodromou, Velibor Savic, Laurence H Pearl
Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28557458/design-and-discovery-of-n-2-methyl-5-morpholino-6-tetrahydro-2h-pyran-4-yl-oxy-3-3-bipyridin-5-yl-3-trifluoromethyl-benzamide-raf709-a-potent-selective-and-efficacious-raf-inhibitor-targeting-ras-mutant-cancers
#3
Gisele A Nishiguchi, Alice Rico, Huw Tanner, Robert J Aversa, Benjamin R Taft, Sharadha Subramanian, Lina Setti, Matthew T Burger, Lifeng Wan, Victoriano Tamez, Aaron Smith, Yan Lou, Paul A Barsanti, Brent A Appleton, Mulugeta Mamo, Laura Tandeske, Ina Dix, John E Tellew, Shenlin Huang, Lesley A Mathews Griner, Vesselina G Cooke, Anne Van Abbema, Hanne Merritt, Sylvia Ma, Kalyani Gampa, Fei Feng, Jing Yuan, Yingyun Wang, Jacob R Haling, Sepideh Vaziri, Mohammad Hekmat-Nejad, Johanna M Jansen, Valery Polyakov, Richard Zang, Vijay Sethuraman, Payman Amiri, Mallika Singh, Emma Lees, Wenlin Shao, Darrin D Stuart, Michael P Dillon, Savithri Ramurthy
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation ...
June 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28536078/akt-is-critically-involved-in-the-antagonism-of-braf-inhibitor-sorafenib-against-dabrafenib-in-colorectal-cancer-cells-harboring-both-wild-type-and-mutant-v600e-braf-genes
#4
Hongbin Wang, Haitian Quan, Liguang Lou
BRAF, one of the key factors in mitogen-activated protein kinase (MAPK) signaling pathway, plays an important role in cell functions including growth and proliferation. Inhibition of BRAF represents a promising antitumor strategy. Dabrafenib, a type I inhibitor of BRAF interrupting RAF/MEK interaction, has been approved by FDA as a single agent or combined with MEK inhibitor trametinib for the treatment of patients with BRAF V600E mutation-positive advanced melanoma. In the present study, we investigated the feasibility of combined treatment with dabrafenib and sorafenib, type I and type II BRAF inhibitor respectively, on colorectal cancer cells with BRAF V600E mutation...
July 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28497782/raf-proteins-exert-both-specific-and-compensatory-functions-during-tumour-progression-of-nras-driven-melanoma
#5
Coralie Dorard, Charlène Estrada, Céline Barbotin, Magalie Larcher, Alexandra Garancher, Jessy Leloup, Friedrich Beermann, Manuela Baccarini, Celio Pouponnot, Lionel Larue, Alain Eychène, Sabine Druillennec
NRAS and its effector BRAF are frequently mutated in melanoma. Paradoxically, CRAF but not BRAF was shown to be critical for various RAS-driven cancers, raising the question of the role of RAF proteins in NRAS-induced melanoma. Here, using conditional ablation of Raf genes in NRAS-induced mouse melanoma models, we investigate their contribution in tumour progression, from the onset of benign tumours to malignant tumour maintenance. We show that BRAF expression is required for ERK activation and nevi development, demonstrating a critical role in the early stages of NRAS-driven melanoma...
May 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28485964/potent-pan-raf-and-receptor-tyrosine-kinase-inhibitors-based-on-a-cyclopropyl-formamide-fragment-overcome-resistance
#6
Yanmin Zhang, Lu Wang, Qing Zhang, Gaoyuan Zhu, Zhimin Zhang, Xiang Zhou, Yadong Chen, Tao Lu, Weifang Tang
While selective BRaf(V600E) inhibitors have been proven effective clinically, acquired resistance rapidly develops through reactivation of the mitogen-activated protein kinase (MAPK) pathway. Simultaneous targeting of multiple nodes in the pathway offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Replacement pyridine group of Y-1 by a cyclopropyl formamide group afforded I-01 as a novel multitargeted kinase inhibitor template. I-01 displayed enzyme potency against Pan-Raf and receptor tyrosine kinases (RTKs)...
June 26, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28414306/targeting-prohibitins-with-chemical-ligands-inhibits-kras-mediated-lung-tumours
#7
H Yurugi, F Marini, C Weber, K David, Q Zhao, H Binder, L Désaubry, K Rajalingam
KRAS is one of the most frequently mutated oncogenes in human non-small cell lung cancers (NSCLCs). RAS proteins trigger multiple effector signalling pathways including the highly conserved RAF-MAPK pathway. CRAF, a direct RAS effector protein, is required for KRAS-mediated tumourigenesis. Thus, the molecular mechanisms driving the activation of CRAF are intensively studied. Prohibitin 1 (PHB1) is an evolutionarily conserved adaptor protein and interaction of CRAF with PHB1 at the plasma membrane is essential for CRAF activation...
April 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28382170/obatoclax-and-ly3009120-efficiently-overcome-vemurafenib-resistance-in-differentiated-thyroid-cancer
#8
Wei-Jun Wei, Zhen-Kui Sun, Chen-Tian Shen, Hong-Jun Song, Xin-Yun Zhang, Zhong-Ling Qiu, Quan-Yong Luo
Although the prognosis of differentiated thyroid cancer (DTC) is relatively good, 30-40% of patients with distant metastases develop resistance to radioactive iodine therapy due to tumor dedifferentiation. For DTC patients harboring BRAF(V600E) mutation, Vemurafenib, a BRAF kinase inhibitor, has dramatically changed the therapeutic landscape, but side effects and drug resistance often lead to termination of the single agent treatment. In the present study, we showed that either LY3009120 or Obatoclax (GX15-070) efficiently inhibited cell cycle progression and induced massive death of DTC cells...
2017: Theranostics
https://www.readbyqxmd.com/read/28368067/rational-design-synthesis-and-biological-evaluation-of-pan-raf-inhibitors-to-overcome-resistance
#9
Lu Wang, Gaoyuan Zhu, Qing Zhang, Chunqi Duan, Yanmin Zhang, Zhimin Zhang, Yujun Zhou, Tao Lu, Weifang Tang
Selective BRaf(V600E) inhibitors with DFG-in conformation have been proven effective against a subset of melanoma. However, representative inhibitor vemurafenib rapidly acquires resistance in the BRaf(WT) cells through a CRaf or BRaf(WT) dependent manner. Simultaneous targeting of all subtypes of Raf proteins offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Herein, we describe the design and characterization of a series of compounds I-01-I-22, based on a pyrimidine scaffold with DFG-out conformation as Pan-Raf inhibitors...
April 18, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28295395/monte-carlo-calculation-of-conversion-coefficients-for-dose-estimation-in-mammography-based-on-a-3d-detailed-breast-model
#10
Wenjing Wang, Rui Qiu, Li Ren, Huan Liu, Zhen Wu, Chunyan Li, Yantao Niu, Junli Li
PURPOSE: At present, the Chinese specification for testing of quality control in x-ray mammography is based on a simple breast model, and does not consider the glandular tissue distribution in the breast. In order to more precisely estimate the mean glandular dose (MGD) in mammography for Chinese women, a three-dimensional (3D) detailed breast model based on realistic structures in the breast and Chinese female breast parameters was built and applied in this study. METHODS: To characterize the Chinese female breast, Chinese female breast parameters including breast size, compressed breast thickness (CBT), and glandular content were investigated in this study...
March 14, 2017: Medical Physics
https://www.readbyqxmd.com/read/28281933/spatial-regulation-of-araf-controls-the-mst2-hippo-pathway
#11
Jens Rauch, Walter Kolch
The RAF-MAPK signaling pathway regulates several very diverse cellular processes such as proliferation, differentiation, apoptosis, and transformation. While the canonical function of RAF kinases within the MAPK pathway is the activation of MEK, our group could demonstrate an important crosstalk between RAF signaling and the pro-apoptotic mammalian sterile 20-like kinase (MST2) tumor suppressor pathway in several cancer entities, including head and neck, colon, and breast. Here, the RAF kinases CRAF and ARAF sequester and inhibit the pro-apoptotic kinase MST2 independently of their own kinase activity...
March 10, 2017: Small GTPases
https://www.readbyqxmd.com/read/28272757/aldosterone-activates-the-oncogenic-signals-erk1-2-and-stat3-via-redox-regulated-mechanisms
#12
Nina Queisser, Nicole Schupp, Eva Schwarz, Christina Hartmann, Gerardo G Mackenzie, Patricia I Oteiza
Epidemiological studies found an increased risk for kidney cancer in hypertensive patients, of which a subgroup has high aldosterone (Ald) levels. We recently showed that Ald is genotoxic both in kidney tubular cells and in rats with mineralocorticoid-mediated hypertension. The present work investigated in vitro and in vivo, if the oxidative stress-mediated activation of the ERK1/2 pathway, and its downstream target STAT3, could be one mechanism involved in the potential oncogenic capability of excess Ald exposure...
March 8, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/27999210/ly3009120-a-panraf-inhibitor-has-significant-anti-tumor-activity-in-braf-and-kras-mutant-preclinical-models-of-colorectal-cancer
#13
Eliza Vakana, Susan Pratt, Wayne Blosser, Michele Dowless, Nicholas Simpson, Xiu-Juan Yuan, Susan Jaken, Jason Manro, Jennifer Stephens, Youyan Zhang, Lysiane Huber, Sheng-Bin Peng, Louis F Stancato
Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/27936046/the-ras-effector-interface-isoform-specific-differences-in-the-effector-binding-regions
#14
Hossein Nakhaeizadeh, Ehsan Amin, Saeideh Nakhaei-Rad, Radovan Dvorsky, Mohammad Reza Ahmadian
RAS effectors specifically interact with the GTP-bound form of RAS in response to extracellular signals and link them to downstream signaling pathways. The molecular nature of effector interaction by RAS is well-studied but yet still incompletely understood in a comprehensive and systematic way. Here, structure-function relationships in the interaction between different RAS proteins and various effectors were investigated in detail by combining our in vitro data with in silico data. Equilibrium dissociation constants were determined for the binding of HRAS, KRAS, NRAS, RRAS1 and RRAS2 to both the RAS binding (RB) domain of CRAF and PI3Kα, and the RAS association (RA) domain of RASSF5, RALGDS and PLCε, respectively, using fluorescence polarization...
2016: PloS One
https://www.readbyqxmd.com/read/27890930/histone-deacetylase-inhibitors-interrupt-hsp90%C3%A2-rasgrp1-and-hsp90%C3%A2-craf-interactions-to-upregulate-bim-and-circumvent-drug-resistance-in-lymphoma-cells
#15
H Ding, K L Peterson, C Correia, B Koh, P A Schneider, G S Nowakowski, S H Kaufmann
Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo...
July 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27846237/integrated-genomics-identifies-mir-32-mcl-1-pathway-as-a-critical-driver-of-melanomagenesis-implications-for-mir-replacement-and-combination-therapy
#16
Prasun J Mishra, Pravin J Mishra, Glenn Merlino
AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous...
2016: PloS One
https://www.readbyqxmd.com/read/27820802/inhibition-of-ras-function-through-targeting-an-allosteric-regulatory-site
#17
Russell Spencer-Smith, Akiko Koide, Yong Zhou, Raphael R Eguchi, Fern Sha, Priyanka Gajwani, Dianicha Santana, Ankit Gupta, Miranda Jacobs, Erika Herrero-Garcia, Jacqueline Cobbert, Hugo Lavoie, Matthew Smith, Thanashan Rajakulendran, Evan Dowdell, Mustafa Nazir Okur, Irina Dementieva, Frank Sicheri, Marc Therrien, John F Hancock, Mitsuhiko Ikura, Shohei Koide, John P O'Bryan
RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1...
January 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/27753529/cyclin-g2-promotes-cell-cycle-arrest-in-breast-cancer-cells-responding-to-fulvestrant-and-metformin-and-correlates-with-patient-survival
#18
Maike Zimmermann, Aruni P S Arachchige-Don, Michaela S Donaldson, Tommaso Patriarchi, Mary C Horne
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest...
December 2016: Cell Cycle
https://www.readbyqxmd.com/read/27703006/bipartite-role-of-heat-shock-protein-90-hsp90-keeps-craf-kinase-poised-for-activation
#19
Shahana Mitra, Baijayanti Ghosh, Nilanjan Gayen, Joydeep Roy, Atin K Mandal
CRAF kinase maintains cell viability, growth, and proliferation by participating in the MAPK pathway. Unlike BRAF, CRAF requires continuous chaperoning by Hsp90 to retain MAPK signaling. However, the reason behind the continuous association of Hsp90 with CRAF is still elusive. In this study, we have identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27678303/erianin-inhibits-high-glucose-induced-retinal-angiogenesis-via-blocking-erk1-2-regulated-hif-1%C3%AE-vegf-vegfr2-signaling-pathway
#20
Zengyang Yu, Tianyu Zhang, Chenyuan Gong, Yuchen Sheng, Bin Lu, Lingyu Zhou, Lili Ji, Zhengtao Wang
Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells...
September 28, 2016: Scientific Reports
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