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BH3 mimetics

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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/28319809/abt-737-synergizes-with-cisplatin-bypassing-aberration-of-apoptotic-pathway-in-non-small-cell-lung-cancer
#2
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/28288819/multifaceted-anticancer-activity-of-bh3-mimetics-current-evidence-and-future-prospects
#3
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 10, 2017: Biochemical Pharmacology
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
#4
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/28259821/inhibition-of-mapkinase-pathway-sensitizes-thyroid-cancer-cells-to-abt-737-induced-apoptosis
#5
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
#6
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/28209992/from-basic-apoptosis-discoveries-to-advanced-selective-bcl-2-family-inhibitors
#7
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/28187446/targeting-of-apoptotic-pathways-by-smac-or-bh3-mimetics-distinctly-sensitizes-paclitaxel-resistant-triple-negative-breast-cancer-cells
#8
Effrosini G Panayotopoulou, Anna-Katharina Müller, Melanie Börries, Hauke Busch, Guohong Hu, Sima Lev
Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28182005/constitutive-p53-heightens-mitochondrial-apoptotic-priming-and-favors-cell-death-induction-by-bh3-mimetic-inhibitors-of-bcl-xl
#9
J Le Pen, L Maillet, K Sarosiek, C Vuillier, F Gautier, S Montessuit, J C Martinou, A Letaï, F Braun, P P Juin
No abstract text is available yet for this article.
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28170214/determinants-of-bh3-sequence-specificity-for-the-disruption-of-bcl-xl-cbid-complexes-in-membranes
#10
Kushal Kumar Das, Raed Shalaby, Ana J García-Sáez
The prosurvival Bcl-2 proteins exhibit a specific pattern of interactions with BH3-only proteins that determines the cellular dependence to apoptotic stress. This specificity is crucial for the development of BH3 mimetics, a class of anti-cancer molecules based on the BH3 domain with promising activity in clinical trials. Although complex formation mainly takes place in the mitochondrial outer membrane, most studies so far addressed the interaction between BH3 peptides and truncated Bcl-2 proteins in solution...
February 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28161988/therapeutic-inhibition-of-bcl-2-and-related-family-members
#11
REVIEW
Michelle A Levy, David F Claxton
BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family...
March 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28140720/pathways-and-mechanisms-of-venetoclax-resistance
#12
Prithviraj Bose, Varsha Gandhi, Marina Konopleva
The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax...
January 31, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28134252/thz1-targeting-cdk7-suppresses-stat-transcriptional-activity-and-sensitizes-t-cell-lymphomas-to-bcl2-inhibitors
#13
Florencia Cayrol, Pannee Praditsuktavorn, Tharu M Fernando, Nicholas Kwiatkowski, Rosella Marullo, M Nieves Calvo-Vidal, Jude Phillip, Benet Pera, Shao Ning Yang, Kaipol Takpradit, Lidia Roman, Marcello Gaudiano, Ramona Crescenzo, Jia Ruan, Giorgio Inghirami, Tinghu Zhang, Graciela Cremaschi, Nathanael S Gray, Leandro Cerchietti
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R...
January 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28120212/ym155-enhances-abt-737-mediated-apoptosis-through-mcl-1-downregulation-in-mcl-1-overexpressed-cancer-cells
#14
Seon Min Woo, Kyoung-Jin Min, Bo Ram Seo, Young Ho Seo, Yong-Jin Jeong, Taeg Kyu Kwon
ABT-737 is a BH3 mimetic inhibitor of Bcl-xL, Bcl-2, and Bcl-w, and it has been reported for anti-cancer effects in various types of cancer cells. However, ABT-737 fails to induce apoptosis in cancer cell with high levels of Mcl-1 expression. The pharmacological survivin inhibitor YM155 has been reported to induce downregulation of Mcl-1 expression. Therefore, we investigated the effect of YM155 to sensitize resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. We found that ABT-737 alone and YM155 alone did not induce apoptosis, but YM155 markedly sensitized ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma cells (U251MG), and human lung carcinoma cells (A549)...
January 24, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28100580/venetoclax-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#15
Andrew W Roberts, Stephan Stilgenbauer, John F Seymour, David C S Huang
Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacological mimic of the proteins that initiate apoptosis (a so-called BH3-mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a Phase 1 study, including complete remissions in 20% of patients...
January 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28094768/bcl-w-has-a-fundamental-role-in-b-cell-survival-and-lymphomagenesis
#16
Clare M Adams, Annette S Kim, Ramkrishna Mitra, John K Choi, Jerald Z Gong, Christine M Eischen
Compromised apoptotic signaling is a prerequisite for tumorigenesis. The design of effective therapies for cancer treatment depends on a comprehensive understanding of the mechanisms that govern cell survival. The antiapoptotic proteins of the BCL-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Unlike BCL-2 and BCL-XL, the closest antiapoptotic relative BCL-W is required for spermatogenesis, but was considered dispensable for all other cell types...
February 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28079887/drp-1-is-required-for-bh3-mimetic-mediated-mitochondrial-fragmentation-and-apoptosis
#17
Mateus Milani, Dominic P Byrne, Georgia Greaves, Michael Butterworth, Gerald M Cohen, Patrick A Eyers, Shankar Varadarajan
The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28074072/targeting-bet-proteins-improves-the-therapeutic-efficacy-of-bcl-2-inhibition-in-t-cell-acute-lymphoblastic-leukemia
#18
S Peirs, V Frismantas, F Matthijssens, W Van Loocke, T Pieters, N Vandamme, B Lintermans, M P Dobay, G Berx, B Poppe, S Goossens, B C Bornhauser, J-P Bourquin, P Van Vlierberghe
Inhibition of anti-apoptotic BCL-2 has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET bromodomain inhibitor JQ1...
January 11, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28055968/bh3-mimetics-suppress-cxcl12-expression-in-human-malignant-peripheral-nerve-sheath-tumor-cells
#19
Christopher D Graham, Niroop Kaza, Hawley C Pruitt, Lauren M Gibson, Barbara J Klocke, Lalita A Shevde, Steven L Carroll, Kevin A Roth
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell-derived neoplasms of the peripheral nervous system that have recently been shown to possess an autocrine CXCL12/CXCR4 signaling loop that promotes tumor cell proliferation and survival. Importantly, the CXCL12/CXCR4 signaling axis is driven by availability of the CXCL12 ligand rather than CXCR4 receptor levels alone. Therefore, pharmacological reduction of CXCL12 expression could be a potential chemotherapeutic target for patients with MPNSTs or other pathologies wherein the CXCL12/CXCR4 signaling axis is active...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28009301/tight-sequestration-of-bh3-proteins-by-bcl-xl-at-subcellular-membranes-contributes-to-apoptotic-resistance
#20
Jessie Pécot, Laurent Maillet, Janic Le Pen, Céline Vuillier, Sophie de Carné Trécesson, Aurélie Fétiveau, Kristopher A Sarosiek, Florian J Bock, Frédérique Braun, Anthony Letai, Stephen W G Tait, Fabien Gautier, Philippe P Juin
Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti-cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems...
December 20, 2016: Cell Reports
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