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https://www.readbyqxmd.com/read/28326661/role-of-single-disulfide-linkages-in-the-folding-and-activity-of-scyllatoxin-based-bh3-domain-mimetics
#1
Danushka Arachchige, M Margaret Harris, Zachary Coon, Jacob Carlsen, Justin M Holub
Anti-apoptotic Bcl-2 proteins are implicated in pathogenic cell survival and have attracted considerable interest as therapeutic targets. We recently developed a class of synthetic peptide based on scyllatoxin (ScTx) designed to mimic the helical BH3 interaction domain of the pro-apoptotic Bcl-2 protein Bax. In this communication, the contribution of single disulfides in the folding and function of ScTx-Bax peptides was investigated. We synthesized five ScTx-Bax variants, each presenting a different combination of native disulfide linkage and evaluated their ability to directly bind Bcl-2 in vitro...
March 22, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28321654/theoretical-insight-into-the-bh3%C3%A2-hcn-adsorption-on-the-co-100-and-co-110-surfaces-as-hydrogen-storage
#2
He Zhao, Fu-de Ren, Yan-Hong Wang
Fifteen configurations and adsorption energies of the adsorption sites of BH3∙∙∙HCN on Co(100) and Co(110) surfaces were investigated using the density functional theory. The results show that after BH3∙∙∙HCN is adsorbed, although there is no general behavior for the H∙∙∙H distances, the adsorption energies of BH3∙∙∙HCN are always far stronger than those of H2 on Co surfaces, suggesting that the dihydrogen-bonded complex, one kind of prospective material for reversible hydrogen storage, can be tightly adsorbed on the surfaces of metals...
April 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#3
Eun Young Kim, Ji Ye Jung, Arum Kim, Yoon Soo Chang, Se Kyu Kim
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28318259/ammonia-borane-clusters-energetics-of-dihydrogen-bonding-cooperativity-and-the-role-of-electrostatics
#4
Kunduchi P Vijayalakshmi, Cherumuttathu H Suresh
Cluster formation of ammonia borane (NH3BH3) driven by noncovalent H···H dihydrogen interaction is investigated at the M06L/6-311+G(d,p) level of density functional theory. For clusters containing up to six monomers, ladder, cyclic, stacked, cross-stacked, end-on, mixed and hexagonal configurations have been screened for their energetic stability. In the dimer, 7.94 kcal/mol stabilization energy per monomer (Em) is observed. Compared to ladder and cyclic configurations, a tetramer consisting of stacked dimer units is more stable by 3...
March 24, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28317183/defective-metal-organic-frameworks-incorporating-ir-based-metallo-ligands-sorption-and-dye-degradation-properties
#5
Li-Min Zheng, Kun Fan, Wei-Xuan Nie, Lu-Ping Wang, Chwen-Haw Liao, Song-Song Bao
Artificial control and engineering of metal-organic framework crystals with defects can endow them with suitable properties for application in gas storage, separation and catalysis. In this work, we synthesized a series of defective Ir-containing metal organic frameworks [Zn4(µ4-O)(Ir-A)2(1-x)(Ir-B)2x] (ZnIr-MOF-dx) by doping heterostructural linker Ir-BH3 into the parent [Zn4(µ4-O)(Ir-A)2] (ZnIr-MOF), where Ir-AH3 represents Ir(ppy-COOH)3 (ppyCOOH = 3-(pyridin-2-yl)benzoic acid) and Ir-BH3 is Ir(ppy-COOH)2(2-pyPO3H) (2-pyPO3H2 = 2-pyridylphosphonic acid)...
March 20, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28288819/multifaceted-anticancer-activity-of-bh3-mimetics-current-evidence-and-future-prospects
#6
REVIEW
Małgorzata Opydo-Chanek, Oscar Gonzalo, Isabel Marzo
BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials...
March 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28287102/plumbagin-sensitizes-breast-cancer-cells-to-tamoxifen-induced-cell-death-through-grp78-inhibition-and-bik-upregulation
#7
Anna Kawiak, Anna Domachowska, Anna Jaworska, Ewa Lojkowska
The glucose regulated protein 78 (GRP78) is a major chaperone of the endoplasmic reticulum, and a prosurvival component of the unfolded protein response. GRP78 is upregulated in many types of cancers, including breast cancer. Research has suggested that GRP78 overexpression confers chemoresistance to anti-estrogen agents through a mechanism involving the inhibition of a pro-apoptotic BH3-only protein, Bik. In the present research the role of plumbagin, a naturally occurring naphthoquinone, in GRP78-associated cell death inhibition was examined...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28279820/binding-affinity-of-pro-apoptotic-bh3-peptides-for-the-anti-apoptotic-mcl-1-and-a1-proteins-molecular-dynamics-simulations-of-mcl-1-and-a1-in-complex-with-six-different-bh3-peptides
#8
Vivek Modi, Ramasubbu Sankararamakrishnan
The anti-apoptotic members of Bcl-2 family of proteins bind to their pro-apoptotic counterparts to induce or prevent cell death.Based on the distinct binding profiles for specific pro-apoptotic BH3 peptides, the anti-apoptotic Bcl-2 proteins can be divided into at least two subclasses. The subclass that includes Bcl-XL binds strongly to Bad BH3 peptide while it has weak binding affinity for the second subclass of Bcl-2 proteins such as Mcl-1 and A1. Anti-apoptotic Bcl-2 proteins are considered to be attractive drug targets for anti-cancer drugs...
February 9, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28277671/enzyme-cleavable-polymeric-micelles-for-the-intracellular-de-livery-of-pro-apoptotic-peptides
#9
Hanna B Kern, Selvi Srinivasan, Anthony J Convertine, David Hockenbery, Oliver W Press, Patrick S Stayton
Peptides derived from the third Bcl-2 homology domain (BH3) renormalize apoptotic signaling by antagonizing pro-survival Bcl-2 family members. They serve as a model for potential peptide drugs that possess therapeutic activities but are limited by delivery barriers including short circulation half-lives and poor penetration into cells. A diblock polymeric micelle carrier for the BIM BH3 peptide was recently described that demonstrated anti-tumor activity in a B-cell lymphoma xenograft model [Berguig et al., Mol Ther, 2015]...
March 9, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28271116/octahedral-manganese-i-and-ruthenium-ii-complexes-containing-2-methylamido-pyridine-borane-as-a-tripod-%C3%AE%C2%BA-3-n-h-h-ligand
#10
Javier Brugos, Javier A Cabeza, Pablo García-Álvarez, Enrique Pérez-Carreño, Juan F Van der Maelen
The borane adduct of the 2-(methylamido)pyridine anion, [mapyBH3](-), has been incorporated into octahedral metal complexes. In fac-[Mn(κ(3)N,H,H-mapyBH3)(CO)3] (1) and fac-[RuH(κ(3)N,H,H-mapyBH3)(CO)(PiPr3)] (2), which have been prepared by treating K[mapyBH3] with fac-[MnBr(MeCN)2(CO)3] and [RuHCl(CO)(PiPr3)2], respectively, it behaves as a tripod ligand, attached to the metal atom through the amido N atom and through two H atoms of the BH3 moiety. X-ray diffraction analyses and theoretical studies (DFT, QTAIM) have shown that the MH2B atom grouping of 1 and 2 comprises two 3c-2e M-H-B interactions that are between those of the Shimoi type (κ(1)H coordination of the B-H bond) and those of the agostic type (κ(2)B,H coordination of the B-H bond)...
March 8, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28259821/inhibition-of-mapkinase-pathway-sensitizes-thyroid-cancer-cells-to-abt-737-induced-apoptosis
#11
Viswanath Gunda, Kristopher A Sarosiek, Eran Brauner, Yon Seon Kim, Salma Amin, Zhiheng Zhou, Antony Letai, Sareh Parangi
Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line...
March 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28252652/bh3-mimetic-elicited-ca-2-signals-in-pancreatic-acinar-cells-are-dependent-on-bax-and-can-be-reduced-by-ca-2-like-peptides
#12
Pawel E Ferdek, Monika A Jakubowska, Polina Nicolaou, Julia V Gerasimenko, Oleg V Gerasimenko, Ole H Petersen
BH3 mimetics are small-molecule inhibitors of B-cell lymphoma-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment...
March 2, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28247997/bcl2-mutations-do-not-confer-adverse-prognosis-in-follicular-lymphoma-patients-treated-with-rituximab
#13
Sarah Huet, Edith Szafer-Glusman, Bruno Tesson, Luc Xerri, Wayne J Fairbrother, Kiran Mukhyala, Chris Bolen, Elizabeth Punnoose, Laurie Tonon, Catherine Chassagne-Clément, Pierre Feugier, Alain Viari, Fabrice Jardin, Gilles Salles, Pierre Sujobert
BCL2 mutations have been suggested to confer an adverse prognosis to follicular lymphoma (FL) patients, but their prognostic value has not been assessed in patients treated with a rituximab-containing regimen. Here we evaluated the prognostic value of BCL2 mutations in a large prospective cohort of 252 FL patients treated with immunochemotherapy in the PRIMA randomized trial. Using a DNA-targeted sequencing approach, we detected amino acid altering mutations in 135 patients (54%) and showed that these mutations were probably mediated by the over-activation of AICDA (Activation-induced cytidine deaminase) in the context of the t(14;18) translocation...
March 1, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28235427/efficient-t3p-%C3%A2-mediated-synthesis-differential-cytotoxicity-and-apoptosis-induction-by-indolo-triazolo-thiadiazoles-in-human-breast-adenocarcinoma-cells
#14
Pooja R Kamath, Dhanya Sunil, Shubhankar Das, Abdul Ajees Abdul Salam, B S Satish Rao
The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P(®) mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells...
February 21, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28223017/novel-bcl2-inhibitor-disarib-induces-apoptosis-by-disruption-of-bcl2-bak-interaction
#15
Supriya V Vartak, Divyaanka Iyer, T R Santhoshkumar, Sheetal Sharma, Archita Mishra, Gunaseelan Goldsmith, Mrinal Srivastava, Shikha Srivastava, Subhas S Karki, Avadhesha Surolia, Bibha Choudhary, Sathees C Raghavan
Apoptosis is a highly regulated pathway of programmed cell death relying on the fine balance between pro and antiapoptotic binding partners. Overexpression of the antiapoptotic protein BCL2 in several cancers makes it an ideal target for chemotherapy, with minimum side effects. In one of our previous studies, we designed, synthesized and characterized Disarib, a BCL2-specific small molecule inhibitor. Interestingly, Disarib showed a novel mode of BCL2 inhibition, by predominantly binding to its BH1 domain, as compared to the BH3-specific action of other known BCL2 inhibitors...
February 20, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28218849/theoretical-study-of-the-heterolytic-%C3%AF-bond-cleavage-on-the-ge%C3%A2-o-bond-of-germanone-an-insight-into-the-driving-force-from-both-electronic-and-dynamical-aspects
#16
Toshiaki Matsubara, Tomoyoshi Ito
The mechanism of the σ bond cleavage of H2O, NH3, Me2C═O, H2, CH4, BH3, and SiH4 on the Ge═O bond of germanone is examined by means of both quantum mechanical (QM) and molecular dynamics (MD) methods. The QM calculations show that the σ bonds of all the substrates are heterolytically broken on the very largely polarized Ge═O bond. Before the σ bond cleavage, the substrate at first approach the Ge═O germanium in the cases of H2O, Me2C═O, and NH3, and in contrast, the Ge═O oxygen in the cases of H2, CH4, BH3, and SiH4...
February 20, 2017: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/28215535/ambra1-a-novel-bh3-like-protein-new-insights-into-the-ambra1-bcl2-family-proteins-relationship
#17
A Di Rita, F Strappazzon
Cellular homeostasis swings like a pendulum backward and forward between life and death. Two of the main processes, which regulate this equilibrium, are autophagy and apoptosis. While autophagy is a highly conserved self-digestion mechanism that mediates degradation of damaged or surplus components, apoptosis is a programmed cell suicide in which typical death signals induce the elimination of undesired cells. Both these processes are highly regulated by complex molecular machineries, including some common proteins whose "dual role" favors one process or the other...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28209992/from-basic-apoptosis-discoveries-to-advanced-selective-bcl-2-family-inhibitors
#18
REVIEW
Avi Ashkenazi, Wayne J Fairbrother, Joel D Leverson, Andrew J Souers
Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XL dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer...
February 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28202514/mcl-1-degradation-is-required-for-targeted-therapeutics-to-eradicate-colon-cancer-cells
#19
Jingshan Tong, Peng Wang, Shuai Tan, Dongshi Chen, Zaneta Nikolovska-Coleska, Fangdong Zou, Jian Yu, Lin Zhang
The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#20
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
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