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https://www.readbyqxmd.com/read/28927801/design-synthesis-and-antitumor-activity-of-novel-sorafenib-derivatives-bearing-pyrazole-scaffold
#1
Min Wang, Shan Xu, Huajun Lei, Caolin Wang, Zhen Xiao, Shuang Jia, Jia Zhi, Pengwu Zheng, Wufu Zhu
Four series of Sorafenib derivatives bearing pyrazole scaffold (8a-m, 9a-c, 10a-e and 11a) were synthesized and characterized by NMR and MS. All of the target compounds were evaluated for the cytotoxicity against A549, HepG2, MCF-7, and PC-3 cancer cell lines and some selected compounds were further evaluated for the activity against VEGFR-2/KDR, BRAF, CRAF, c-Met, EGFR and Flt-3 kinases. Compounds 8b and 8i were more active than that of compounds 8h, 9a, especially the IC50 value of compounds 8b on VEGFR-2 kinase was 0...
September 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28914097/advanced-glycation-end-products-interfere-in-luteinizing-hormone-and-follicle-stimulating-hormone-signaling-in-human-granulosa-kgn-cells
#2
Eleni A Kandaraki, Antonios Chatzigeorgiou, Efstathia Papageorgiou, Christina Piperi, Christos Adamopoulos, Athanasios G Papavassiliou, Michael Koutsilieris, Evanthia Diamanti-Kandarakis
Advanced glycation end products accumulate in the ovarian granulosa-cell layer of women with polycystic ovarian syndrome. Taken that the MAPK/ERK-pathway is a key regulator of oocyte maturation and function, consisting the main pathway used by the gonadotrophic hormones (luteinizing hormone, follicle stimulating hormone) to control ovulation, the present study aims to assess advanced glycation end products' interference into luteinizing hormone-and follicle stimulating hormone-signaling via the MAPK/ERK-pathway in the human granulosa KGN cell line...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28857077/fusions-in-solid-tumours-diagnostic-strategies-targeted-therapy-and-acquired-resistance
#3
REVIEW
Alison M Schram, Matthew T Chang, Philip Jonsson, Alexander Drilon
Structural gene rearrangements resulting in gene fusions are frequent events in solid tumours. The identification of certain activating fusions can aid in the diagnosis and effective treatment of patients with tumours harbouring these alterations. Advances in the techniques used to identify fusions have enabled physicians to detect these alterations in the clinic. Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions...
August 31, 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/28819643/membrane-localization-of-acetylated-cnk1-mediates-a-positive-feedback-on-raf-erk-signaling
#4
Adrian Fischer, Wignand W D Mühlhäuser, Bettina Warscheid, Gerald Radziwill
Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)-binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1...
August 2017: Science Advances
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#5
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28783725/a-braf-kinase-inactive-mutant-induces-lung-adenocarcinoma
#6
Patricia Nieto, Chiara Ambrogio, Laura Esteban-Burgos, Gonzalo Gómez-López, María Teresa Blasco, Zhan Yao, Richard Marais, Neal Rosen, Roberto Chiarle, David G Pisano, Mariano Barbacid, David Santamaría
The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis...
August 10, 2017: Nature
https://www.readbyqxmd.com/read/28783719/tumours-with-class-3-braf-mutants-are-sensitive-to-the-inhibition-of-activated-ras
#7
Zhan Yao, Rona Yaeger, Vanessa S Rodrik-Outmezguine, Anthony Tao, Neilawattie M Torres, Matthew T Chang, Matthias Drosten, Huiyong Zhao, Fabiola Cecchi, Todd Hembrough, Judith Michels, Hervé Baumert, Linde Miles, Naomi M Campbell, Elisa de Stanchina, David B Solit, Mariano Barbacid, Barry S Taylor, Neal Rosen
Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling...
August 2, 2017: Nature
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
#8
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...
August 15, 2017: Life Sciences
https://www.readbyqxmd.com/read/28636940/hectd3-mediates-an-hsp90-dependent-degradation-pathway-for-protein-kinase-clients
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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...
August 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28382170/obatoclax-and-ly3009120-efficiently-overcome-vemurafenib-resistance-in-differentiated-thyroid-cancer
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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