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Birinapant

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https://www.readbyqxmd.com/read/27520705/iap-antagonists-birinapant-and-at-406-efficiently-synergise-with-either-trail-braf-or-bcl-2-inhibitors-to-sensitise-brafv600e-colorectal-tumour-cells-to-apoptosis
#1
Philippos Perimenis, Apostolos Galaris, Alexandra Voulgari, Margarita Prassa, Alexander Pintzas
BACKGROUND: High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs. METHODS: In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols...
2016: BMC Cancer
https://www.readbyqxmd.com/read/27469115/smac-mimetic-birinapant-plus-radiation-eradicates-human-head-and-neck-cancers-with-genomic-amplifications-of-cell-death-genes-fadd-and-birc2
#2
Danielle F Eytan, Grace E Snow, Sophie Carlson, Adeeb Derakhshan, Anthony Saleh, Stephen Schiltz, Hui Cheng, Suresh Mohan, Shaleeka Cornelius, Jamie Coupar, Anastasia L Sowers, Lidia Hernandez, James B Mitchell, Christina M Annunziata, Zhong Chen, Carter Van Waes
Comparison of tumors from The Cancer Genome Atlas (TCGA) reveals that head and neck squamous cell carcinomas (HNSCC) harbor the most frequent genomic amplifications of Fas-associated death domain (FADD), with or without Baculovirus inhibitor of apoptosis repeat containing BIRC2 (cIAP1), affecting about 30% of patients in association with worse prognosis. Here, we identified HNSCC cell lines harboring FADD/BIRC2 amplifications and overexpression by exome sequencing, RT-PCR, and Western blotting. In vitro, FADD or BIRC2 siRNA knockdown inhibited HNSCC displaying amplification and increased expression of these genes, supporting their functional importance in promoting proliferation...
September 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/27302164/acute-sensitivity-of-ph-like-acute-lymphoblastic-leukemia-to-the-smac-mimetic-birinapant
#3
Jennifer Richmond, Alissa Robbins, Kathryn Evans, Dominik Beck, Raushan T Kurmasheva, Catherine A Billups, Hernan Carol, Sue Heatley, Rosemary Sutton, Glenn M Marshall, Deborah White, John Pimanda, Peter J Houghton, Malcolm A Smith, Richard B Lock
Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL...
August 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27272773/birinapant-tl32711-improves-responses-to-gem-azd7762-combination-therapy-in-triple-negative-breast-cancer-cell-lines
#4
Dong-Joon Min, Siping He, Jeffrey E Green
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer currently lacking targeted therapies. Our previous work demonstrated a therapeutic synergism with gemcitabine (GEM) and the CHK1 inhibitor (AZD7762) combination treatment in a TNBC cell line. We hypothesized that the response to this combination therapy would differ among heterogeneous TNBC patients and that addition of a SMAC mimetic (TL32711) could improve efficacy. MATERIALS AND METHODS: Therapeutic responses to GEM, GEM/AZD7762, and GEM/AZD7762/TL32711 combinations were investigated by XTT assays and western blotting of cell cycle and apoptosis-related proteins in ten TNBC cell lines...
June 2016: Anticancer Research
https://www.readbyqxmd.com/read/27194728/activation-of-concurrent-apoptosis-and-necroptosis-by-smac-mimetics-for-the-treatment-of-refractory-and-relapsed-all
#5
Scott McComb, Júlia Aguadé-Gorgorió, Lena Harder, Blerim Marovca, Gunnar Cario, Cornelia Eckert, Martin Schrappe, Martin Stanulla, Arend von Stackelberg, Jean-Pierre Bourquin, Beat C Bornhauser
More precise treatment strategies are urgently needed to decrease toxicity and improve outcomes for treatment-refractory leukemia. We used ex vivo drug response profiling of high-risk, relapsed, or refractory acute lymphoblastic leukemia (ALL) cases and identified a subset with exquisite sensitivity to small-molecule mimetics of the second mitochondria-derived activator of caspases (SMAC) protein. Potent ex vivo activity of the SMAC mimetic (SM) birinapant correlated with marked in vivo antileukemic effects, as indicated by delayed engraftment, decreased leukemia burden, and prolonged survival of xenografted mice...
May 18, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27194727/the-caspase-8-inhibitor-emricasan-combines-with-the-smac-mimetic-birinapant-to-induce-necroptosis-and-treat-acute-myeloid-leukemia
#6
Gabriela Brumatti, Chunyan Ma, Najoua Lalaoui, Nhu-Y Nguyen, Mario Navarro, Maria C Tanzer, Jennifer Richmond, Margherita Ghisi, Jessica M Salmon, Natasha Silke, Giovanna Pomilio, Stefan P Glaser, Elisha de Valle, Raffi Gugasyan, Mark A Gurthridge, Stephen M Condon, Ricky W Johnstone, Richard Lock, Guy Salvesen, Andrew Wei, David L Vaux, Paul G Ekert, John Silke
Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant...
May 18, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/26985322/electrophilic-oxidation-and-1-2-rearrangement-of-the-biindole-core-of-birinapant
#7
Yijun Deng, Thomas Haimowitz, Matthew G LaPorte, Susan R Rippin, Matthew D Alexander, Pavan Tirunahari Kumar, Mukta S Hendi, Yu-Hua Lee, Stephen M Condon
Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo...
March 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/26944210/cotreatment-with-smac-mimetics-and-demethylating-agents-induces-both-apoptotic-and-necroptotic-cell-death-pathways-in-acute-lymphoblastic-leukemia-cells
#8
Steve Gerges, Katharina Rohde, Simone Fulda
Treatment resistance in acute lymphoblastic leukemia (ALL) is often caused by defects in programmed cell death, e.g. by overexpression of Inhibitor of Apoptosis (IAP) proteins. Here, we report that small-molecule Smac mimetics (i.e. BV6, LCL161, birinapant) that neutralize x-linked IAP (XIAP), cellular IAP (cIAP)1 and cIAP2 cooperate with demethylating agents (i.e. 5-azacytidine (5AC) or 5-aza-2'-deoxycytidine (DAC)) to induce cell death in ALL cells. Molecular studies reveal that induction of cell death is preceded by BV6-mediated depletion of cIAP1 protein and involves tumor necrosis factor (TNF)α autocrine/paracrine signaling, since the TNFα-blocking antibody Enbrel significantly reduces BV6/5AC-induced cell death...
May 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26859455/targeting-p38-or-mk2-enhances-the-anti-leukemic-activity-of-smac-mimetics
#9
Najoua Lalaoui, Kay Hänggi, Gabriela Brumatti, Diep Chau, Nhu-Y N Nguyen, Lazaros Vasilikos, Lisanne M Spilgies, Denise A Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M Salmon, Geoffrey M Matthews, Elisha de Valle, Donia M Moujalled, Manoj B Menon, Sukhdeep Kaur Spall, Stefan P Glaser, Jennifer Richmond, Richard B Lock, Stephen M Condon, Raffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W Johnstone, Lenka Munoz, Andrew Wei, Paul G Ekert, David L Vaux, W Wei-Lynn Wong, John Silke
Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM...
February 8, 2016: Cancer Cell
https://www.readbyqxmd.com/read/26657652/patient-derived-glioblastoma-cells-show-significant-heterogeneity-in-treatment-responses-to-the-inhibitor-of-apoptosis-protein-antagonist-birinapant
#10
Z Zakaria, A Tivnan, L Flanagan, D W Murray, M Salvucci, B W Stringer, B W Day, A W Boyd, D Kögel, M Rehm, D F O'Brien, A T Byrne, J H M Prehn
BACKGROUND: Resistance to temozolomide (TMZ) greatly limits chemotherapeutic effectiveness in glioblastoma (GBM). Here we analysed the ability of the Inhibitor-of-apoptosis-protein (IAP) antagonist birinapant to enhance treatment responses to TMZ in both commercially available and patient-derived GBM cells. METHODS: Responses to TMZ and birinapant were analysed in a panel of commercial and patient-derived GBM cell lines using colorimetric viability assays, flow cytometry, morphological analysis and protein expression profiling of pro- and antiapoptotic proteins...
January 19, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/26567362/promises-and-challenges-of-smac-mimetics-as-cancer-therapeutics
#11
REVIEW
Simone Fulda
Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents...
November 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26566079/pharmacodynamic-markers-and-clinical-results-from-the-phase-2-study-of-the-smac-mimetic-birinapant-in-women-with-relapsed-platinum-resistant-or-refractory-epithelial-ovarian-cancer
#12
Anne M Noonan, Kristen P Bunch, Jin-Qiu Chen, Michelle A Herrmann, Jung-Min Lee, Elise C Kohn, Ciara C O'Sullivan, Elizabeth Jordan, Nicole Houston, Naoko Takebe, Robert J Kinders, Liang Cao, Cody J Peer, W Douglas Figg, Christina M Annunziata
BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODS: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles...
February 15, 2016: Cancer
https://www.readbyqxmd.com/read/26446940/effect-of-a-smac-mimetic-tl32711-birinapant-on-the-apoptotic-program-and-apoptosis-biomarkers-examined-with-validated-multiplex-immunoassays-fit-for-clinical-use
#13
Apurva K Srivastava, Soumya Jaganathan, Laurie Stephen, Melinda G Hollingshead, Adam Layhee, Eric Damour, Jeevan Prasaad Govindharajulu, Jennifer Donohue, Dominic Esposito, James P Mapes, Robert J Kinders, Naoko Takebe, Joseph E Tomaszewski, Shivaani Kummar, James H Doroshow, Ralph E Parchment
PURPOSE: To support clinical pharmacodynamic evaluation of the Smac mimetic TL32711 (birinapant) and other apoptosis-targeting drugs, we describe the development, validation, and application of novel immunoassays for 15 cytosolic and membrane-associated proteins indicative of the induction, onset, and commitment to apoptosis in human tumors. EXPERIMENTAL DESIGN: The multiplex immunoassays were constructed on the Luminex platform with apoptosis biomarkers grouped into three panels...
February 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26333381/a-phase-i-study-of-the-smac-mimetic-birinapant-in-adults-with-refractory-solid-tumors-or-lymphoma
#14
Ravi K Amaravadi, Russell J Schilder, Lainie P Martin, Myron Levin, Martin A Graham, David E Weng, Alex A Adjei
The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic...
November 2015: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/26282728/smac-derived-aza-peptide-as-an-aminopeptidase-resistant-xiap-bir3-antagonist
#15
Mohamed A Elsawy, Irina G Tikhonova, Lorraine Martin, Brian Walker
The peptidic nature of anti-IAPs N-terminus Smac-derived peptides precludes their utilization as potential therapeutic anticancer agents. Recent advances in the development of novel Smacderived peptidomimetics and non-peptidic molecules with improved anti-IAPs activity and resistance to proteolytic cleavage have been reported and led to a number of candidates that are currently in clinical trials including LCL-161, SM-406/AT-406, GDC-0512/GDC-0917, and birinapant. As an attempt to improve the proteolytic stability of Smac peptides, we developed the Aza-peptide AzaAla- Val-Pro-Phe-Tyr-NH2 (2)...
2015: Protein and Peptide Letters
https://www.readbyqxmd.com/read/26267799/discovery-of-novel-potent-and-specific-cell-death-inducers-in-the-jurkat-acute-lymphoblastic-leukemia-cell-line
#16
Emanuele Carosati, Natascha van den Höfel, Manuela Reif, Giuseppe Marco Randazzo, Bettina Stanitzki, Julia Stevens, Helmut E Gabbert, Gabriele Cruciani, Raimund Mannhold, Csaba Mahotka
The limited clinical efficacy of many cancer therapeutics has initiated intense research efforts toward the discovery of novel chemical entities in this field. In this study, 31 hit candidates were selected from nearly 800,000 database compounds in a ligand-based virtual screening campaign. In turn, three of these hits were found to have (sub)micromolar potencies in proliferation assays with the Jurkat acute lymphatic leukemic cell line. In this assay, the three hits were found to exhibit higher potency than clinically tested cell-death inducers (GDC-0152, AT-406, and birinapant)...
October 2015: ChemMedChem
https://www.readbyqxmd.com/read/26252969/mechanism-based-mathematical-modeling-of-combined-gemcitabine-and-birinapant-in-pancreatic-cancer-cells
#17
Xu Zhu, Robert M Straubinger, William J Jusko
Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs...
October 2015: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/26234182/an-apoptosis-enhancing-drug-overcomes-platinum-resistance-in-a-tumour-initiating-subpopulation-of-ovarian-cancer
#18
D M Janzen, E Tiourin, J A Salehi, D Y Paik, J Lu, M Pellegrini, S Memarzadeh
High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population...
2015: Nature Communications
https://www.readbyqxmd.com/read/26095377/smac-derived-aza-peptide-as-an-aminopeptidase-resistant-xiap-bir3-antagonist
#19
Mohamed A Elsawy, Irina G Tikhonova, S Lorraine Martin, Brian Walker
The peptidic nature of anti-IAPs N-terminus Smac-derived peptides precludes their utilization as potential therapeutic anticancer agents. Recent advances in the development of novel Smac-derived peptidomimetics and non-peptidic molecules with improved anti-IAPs activity and resistance to proteolytic cleavage have been reported and led to a number of candidates that are currently in clinical trials including LCL-161, SM-406/AT-406, GDC-0512/GDC-0917, and birinapant. As an attempt to improve the proteolytic stability of Smac peptides, we developed the Aza-peptide AzaAla-Val-Pro-Phe-Tyr-NH2 (2)...
June 21, 2015: Protein and Peptide Letters
https://www.readbyqxmd.com/read/25902530/eliminating-hepatitis-b-by-antagonizing-cellular-inhibitors-of-apoptosis
#20
Gregor Ebert, Cody Allison, Simon Preston, James Cooney, Jesse G Toe, Michael D Stutz, Samar Ojaimi, Nikola Baschuk, Ueli Nachbur, Joseph Torresi, John Silke, C Glenn Begley, Marc Pellegrini
We have shown that cellular inhibitor of apoptosis proteins (cIAPs) impair clearance of hepatitis B virus (HBV) infection by preventing TNF-mediated killing/death of infected cells. A key question, with profound therapeutic implications, is whether this finding can be translated to the development of drugs that promote elimination of infected cells. Drug inhibitors of cIAPs were developed as cancer therapeutics to promote TNF-mediated tumor killing. These drugs are also known as Smac mimetics, because they mimic the action of the endogenous protein Smac/Diablo that antagonizes cIAP function...
May 5, 2015: Proceedings of the National Academy of Sciences of the United States of America
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