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https://www.readbyqxmd.com/read/28640250/bh3-only-proteins-the-thorny-end-of-the-er-stress-response
#1
Jason A Glab, Marcel Doerflinger, Hamsa Puthalakath
No abstract text is available yet for this article.
June 22, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28622724/porphyrin-arch-tapes-synthesis-contorted-structures-and-full-conjugation
#2
Norihito Fukui, Taeyeon Kim, Dongho Kim, Atsuhiro Osuka
Porphyrin tapes possessing meso-meso β-β β-β triple direct linkages have been targets of extensive studies because of their fully conjugated characteristic π-electronic networks. In this paper, we report porphyrin arch-tapes that bear additional carbonyl group(s) or methylene group(s) inserted between one of the β-β linkage(s) of the porphyrin tapes. The carbonyl-inserted porphyrin arch-tapes were efficiently synthesized by double fusion reactions of β-to-β carbonyl-bridged porphyrin oligomers with DDQ and Sc(OTf)3, and were converted to the methylene-bridged porphyrin arch-tapes via Luche reduction with NaBH4 and CeCl3 followed by ionic hydrogenation with HBF4·OEt2 and BH3·NEt3...
June 23, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28622297/p53-mediated-suppression-of-bip-triggers-bik-induced-apoptosis-during-prolonged-endoplasmic-reticulum-stress
#3
Ignacio López, Anne-Sophie Tournillon, Rodrigo Prado Martins, Konstantinos Karakostis, Laurence Malbert-Colas, Karin Nylander, Robin Fåhraeus
Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6...
June 16, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28617441/concomitant-epigenetic-targeting-of-lsd1-and-hdac-synergistically-induces-mitochondrial-apoptosis-in-rhabdomyosarcoma-cells
#4
Tinka Haydn, Eric Metzger, Roland Schuele, Simone Fulda
The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells...
June 15, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28606806/bcl2-induced-by-lamtor3-mapk-is-a-druggable-target-of-chemoradioresistance-in-mesenchymal-lung-cancer
#5
Ok-Seon Kwon, Soon-Ki Hong, Soo-Jung Kwon, Young-Hyun Go, Ensel Oh, Hyuk-Jin Cha
Mesenchymal-type cancers after epithelial mesenchymal transition (EMT) were recently shown to acquire chemoresistance through expressing EMT specific transcription factors. However, druggable (or actionable) target(s) for chemoresistance in mesenchymal-type lung cancers remain unidentified. Here, we used a public clinical genomic database and mesenchymal lung cancer cells (MLCC) model derived from the A549 lung adenocarcinoma cell line to demonstrate that BCL2 expression, which is highly induced in mesenchymal-type lung cancers, as a predictor of poor prognosis in mesenchymal lung cancer patients and association with acquired chemoradioresistance...
June 10, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28606801/molecular-cloning-characterization-and-expression-analysis-of-b-cell-lymphoma-2-bcl-2-in-the-orange-spotted-grouper-epinephelus-coioides
#6
Sheng-Wei Luo, Huan Kang, Jing-Rong Kong, Ren-Chong Xie, Yuan Liu, Wei-Na Wang, Fu-Xing Xie, Cong Wang, Zuo-Ming Sun
Bcl-2 is a pro-survival member of Bcl-2 like superfamily, playing an important role in regulating the apoptotic process. In this study, the full-length Bcl-2 (EcBcl-2) was obtained, consisting of a 5'UTR of 290 bp, an ORF of 699 bp and a 3'UTR of 920 bp. EcBcl-2 gene encoded a polypeptide of 232 amino acids with an estimated molecular mass of 26.12 KDa and a predicted isoelectric point (pI) of 6.93. The deduced amino acid sequence analysis showed that EcBcl-2 consisted of the conserved residues and characteristic domains known to the critical functionality for Bcl-2...
June 9, 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28605616/managing-patients-with-tp53-deficient-chronic-lymphocytic-leukemia
#7
Jennifer Edelmann, John G Gribben
Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression...
June 2017: Journal of Oncology Practice
https://www.readbyqxmd.com/read/28594323/epistatic-mutations-in-puma-bh3-drive-an-alternate-binding-mode-to-potently-and-selectively-inhibit-anti-apoptotic-bfl-1
#8
Justin M Jenson, Jeremy A Ryan, Robert A Grant, Anthony Letai, Amy E Keating
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs...
June 8, 2017: ELife
https://www.readbyqxmd.com/read/28590071/synthesis-and-characterization-of-nitro-trinitromethyl-and-fluorodinitromethyl-substituted-triazolyl-and-tetrazolyl-trihydridoborate-anions
#9
Guillaume Belanger-Chabot, Max Kaplan, Piyush Deokar, Norbert Szimhardt, Ralf Haiges, Karl O Christe
The problem of preparing energetic, exclusively mono-azolyl substituted hydridoborate anions in high yield and purity from [BH4]- and nitroazoles by hydrogen elimination was overcome by reacting the corresponding nitroazolate anions with the BH3 adducts BH3·S(CH3)2 or BH3·THF. The highly-energetic, nitro-, trinitromethyl-, and fluorodinitromethyl- substituted triazolyl- and tetrazolyl-trihydridoborate anions were synthesized in this manner and characterized by vibrational and multinuclear NMR spectroscopy and their crystal structures...
June 7, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28580107/-phosphanyl-phosphaketenes-as-building-blocks-for-novel-phosphorus-heterocycles
#10
Max M Hansmann, David A Ruiz, Liu Leo Liu, Rodolphe Jazzar, Guy Bertrand
Although BH3 simply coordinates the endocyclic P of (phospholidino)phosphaketene 1(Dipp) , the bulkier B(C6F5)3 gives rise to a zwitterionic diphosphirenium, which is a novel type of 2π-electron aromatic system as shown by the calculated NICS values. While the reaction of 1(Dipp) with Na[PCO(dioxane) x ] is unselective, the same reaction with the sterically bulky (phospholidino)phosphaketene 1(Ar**) [Ar** = 2,6-bis[di(4-tert-butylphenyl)methyl]-4-methylphenyl selectively affords a sodium bridged dimer containing a hitherto unknown λ(3),λ(5),λ(3)-triphosphete core...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28579554/stat3-gain-of-function-mutations-associated-with-autoimmune-lymphoproliferative-syndrome-like-disease-deregulate-lymphocyte-apoptosis-and-can-be-targeted-by-bh3-mimetic-compounds
#11
Schafiq Nabhani, Cyrill Schipp, Hagit Miskin, Carina Levin, Sergey Postovsky, Tal Dujovny, Ariel Koren, Dan Harlev, Anne-Marie Bis, Franziska Auer, Baerbel Keller, Klaus Warnatz, Michael Gombert, Sebastian Ginzel, Arndt Borkhardt, Polina Stepensky, Ute Fischer
Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations...
June 1, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28578655/potential-mechanisms-of-resistance-to-venetoclax-and-strategies-to-circumvent-it
#12
Stephen K Tahir, Morey L Smith, Paul Hessler, Lisa Roberts Rapp, Kenneth B Idler, Chang H Park, Joel D Leverson, Lloyd T Lam
BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges...
June 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28525842/indole-coumarin-thiadiazole-hybrids-an-appraisal-of-their-mcf-7%C3%A2-cell-growth-inhibition-apoptotic-antimetastatic-and-computational-bcl-2-binding-potential
#13
Pooja R Kamath, Dhanya Sunil, Manu M Joseph, Abdul Ajees Abdul Salam, Sreelekha T T
Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells...
May 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#14
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28511583/deciphering-the-crucial-residues-involved-in-heterodimerization-of-bak-peptide-and-anti-apoptotic-proteins-for-apoptosis
#15
Parthiban Marimuthu, Kalaimathy Singaravelu
B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions. This overexpression is modulated or inhibited by heterodimerization of pro-apoptotic BH3 domain or BH3-only peptides to the hydrophobic groove present at the surface of anti-apoptotic proteins...
June 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28489572/ck2-and-pi3k-are-direct-molecular-targets-of-quercetin-in-chronic-lymphocytic-leukaemia
#16
Maria Russo, Alfonsina Milito, Carmela Spagnuolo, Virginia Carbone, Anders Rosén, Paola Minasi, Fabio Lauria, Gian Luigi Russo
Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28489092/reactivity-studies-of-silylene-phc-ntbu-2-c5me5-si-reactions-with-m-cod-cl-2-m-rh-i-ir-i-s-se-te-and-bh3
#17
Sebastian Kaufmann, Sebastian Schäfer, Michael T Gamer, Peter W Roesky
The reactivity of recently introduced N-heterocyclic silylene [PhC(NtBu)2](C5Me5)Si was evaluated. Three different reaction pathways were studied: (1) coordination to a Lewis acid, (2) oxidation by chalcogenides, and (3) coordination to transition metal complexes. The reaction of the silylene with BH3 led to the adduct [PhC(NtBu)2](C5Me5)Si(BH)3. Oxidation with the elemental chalcogens sulphur, selenium, and tellurium resulted in the corresponding silicon(iv)-chalcogenide compounds [PhC(NtBu)2](C5Me5)SiS, [PhC(NtBu)2](C5Me5)SiSe and [PhC(NtBu)2](C5Me5)SiTe...
May 10, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28486749/catalytic-electrophilic-c-h-borylation-using-nhc%C3%A2-boranes-and-iodine-forms-c2-not-c3-borylated-indoles
#18
John S McGough, Jessica Cid, Michael J Ingleson
Activation of N-heterocyclic carbene boranes (NHC⋅BH3 ) by I2 enables the metal-free catalytic C-H borylation of heteroarenes with formation of H2 as the by-product in a process that uses only bench stable precursors. The borylation of indoles using NHC⋅BH3 /I2 produces C2-borylated indoles exclusively in contrast to other catalytic electrophilic C-H borylation methods. Mechanistic studies indicate that this is due to C3 to C2 boron migration facilitated by the absence of exogenous Brønsted bases. Thus this C-H borylation methodology proceeds under sufficiently Brønsted acidic conditions to enable the thermodynamic C2-borylated indole isomer to be formed instead of the C3 borylated-isomer...
May 9, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28469964/comprehensive-pharmacological-profiling-of-neurofibromatosis-cell-lines
#19
Jianman Guo, Michael R Grovola, Hong Xie, Grace E Coggins, Patrick Duggan, Rukhsana Hasan, Jiale Huang, Danny W Lin, Claire Song, Gabriela M Witek, Simon Berritt, David C Schultz, Jeffrey Field
Patients with Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are predisposed to tumors of the nervous system. NF1 patients predominantly develop neurofibromas, and Malignant Peripheral Nerve Sheath Tumors (MPNST) while NF2 patients develop schwannomas and meningiomas. Here we quantified the drug sensitivities of NF1 and NF2 tumor cell lines in a high throughput platform. The platform contained a comprehensive collection of inhibitors of MEK, RAF, RAS, farnesyl transferase, PAK and ERK, representative drugs against many other cancer pathways including Wnt, Hedgehog, p53, EGF, HDAC, as well as classical cytotoxic agents recommended for treating MPNST, such as doxorubicin and etoposide...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#20
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1 Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
May 3, 2017: Molecular Cancer Therapeutics
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