Готові списки джерел за темами / XIAP inhibitors

Добірка наукової літератури з теми "XIAP inhibitors"

Автор: Grafiati
Опубліковано: 7 липня 2024

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Статті в журналах з теми "XIAP inhibitors":

1

Löder, Sandra, Melanie Fakler, Irmela Jeremias, Klaus-Michael Debatin, and Simone Fulda. "XIAP Inhibitors Present a Promising New Strategy to Sensitize Childhood Acute Leukemia Cells for Chemotherapy-Induced Apoptosis." Blood 114, no. 22 (November 20, 2009): 3791. http://dx.doi.org/10.1182/blood.v114.22.3791.3791.

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Abstract Abstract 3791 Poster Board III-727 Children with high risk acute lymphoblastic leukemia (ALL) do not respond well to current treatments. This failure is, at least in part, due to defects in apoptosis programs. Therefore, new strategies are required that counter apoptosis resistance in order to improve the poor prognosis of high risk pediatric acute leukemia. Increasing evidence suggests that high levels of “Inhibitor of Apoptosis” (IAP) proteins may represent a key antiapoptotic mechanism in cancer cells including acute leukemia. Among the IAP family members, it is especially X-linked inhibitor of apoptosis (XIAP) that is known for its antiapoptotic function. Since XIAP blocks apoptosis at a central point of the apoptotic machinery by inhibiting activation of effector caspases, we explored whether XIAP presents a suitable molecular target for therapeutic intervention in childhood leukemia. Here, we report that neutralizing XIAP by small molecule inhibitors is a novel and effective approach to sensitize childhood acute leukemia cells for chemotherapeutic drugs, which are currently used in clinical protocols for the treatment of children with acute leukemia. Subtoxic concentrations of XIAP inhibitors synergize with various anticancer drugs, for example Cytarabine, Vincristine, Doxorubicin, Etoposide and cyclophosphamide, to induce apoptosis in ALL and also in AML cells. By comparison, no sensitization for chemotherapy-induced apoptosis is observed in the presence of a structurally related control compound that only weakly binds to XIAP, demonstrating the specificity of the sensitization effect of XIAP inhibitors. In addition, XIAP inhibitors act in concert with anticancer drugs to reduce clonogenic growth of ALL cells demonstrating that they also suppress long-term survival. Analysis of signaling pathways reveals that XIAP inhibitors enhance chemotherapy-induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase-dependent manner. Further, XIAP inhibitors cause rapid and profound downregulation of cIAP1 accompanied by activation of NF-κB. Of note, inhibition of RIP1 kinase by necrostatin or caspases by the broad range caspase inhibitor zVAD.fmk also significantly reduces the XIAP inhibitor-mediated sensitization to cytotoxic drugs. Intriguingly, the addition of TNFα blocking antibodies also significantly decreases apoptosis upon combined treatment with XIAP inhibitors and chemotherapeutic drugs, indicating that paracrine/autocrine production of TNFα is involved in this synergistic interaction. In support of this notion, addition of soluble recombinant TNFα further increases apoptosis that is induced by XIAP inhibitors and anticancer drugs. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and act in concert with chemotherapeutic drugs to trigger apoptosis. In contrast to malignant cells, XIAP inhibitors at equimolar concentrations alone or in combination with chemotherapeutics are non-toxic to normal peripheral blood lymphocytes, pointing to a therapeutic window. By demonstrating that XIAP inhibitors present a promising novel approach to enhance the efficacy of chemotherapy in childhood acute leukemia, our findings have important implications for the development of innovative treatment strategies to overcome apoptosis resistance in children with high risk leukemia. This approach could be translated into clinical application in childhood ALL, since IAP inhibitors have recently entered evaluation in early clinical trials, thus underscoring the feasibility to incorporate XIAP inhibitors into chemotherapy protocols. Disclosures: No relevant conflicts of interest to declare.
2

Loeder, Sandra, Thorsten Zenz, Andrea Schnaiter, Daniel Mertens, Dirk Winkler, Hartmut Döhner, Klaus-Michael Debatin, Stephan Stilgenbauer, and Simone Fulda. "A Novel Paradigm to Trigger Apoptosis in Chronic Lymphocytic Leukemia." Blood 114, no. 22 (November 20, 2009): 731. http://dx.doi.org/10.1182/blood.v114.22.731.731.

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Abstract Abstract 731 Chronic lymphocytic leukemia (CLL) is characterized by the abnormal accumulation of malignant monoclonal B cells, which has been largely attributed to defective apoptosis rather than aberrant proliferation. This calls for new strategies to re-activate apoptosis programs in CLL in order to develop new therapeutic strategies. “Inhibitor of Apoptosis” (IAP) proteins such as XIAP are aberrantly expressed in many human cancers and block apoptosis at a key node by inhibiting activation of caspases. In the present study, we therefore explored whether targeting XIAP is a suitable strategy to overcome apoptosis resistance of CLL. Here, we provide first evidence that small molecule XIAP inhibitors in combination with the death receptor ligand TRAIL present a novel approach to trigger apoptosis in CLL even in subgroups with resistant disease. Analysis of apoptosis regulatory proteins reveals that XIAP, cIAP1 and cIAP2 are expressed at high levels in primary CLL samples. Proofs of concept studies in CLL cell lines demonstrate that subtoxic concentrations of several distinct XIAP inhibitors significantly enhance TRAIL-induced apoptosis. In addition, XIAP inhibitors sensitize CLL cells for CD95-mediated apoptosis, whereas they have no effect on fludarabine- or chlorambucil-induced apoptosis. This indicates that XIAP inhibitors in particular enhance death receptor-triggered apoptosis in CLL cells. By comparison, no sensitization for death receptor-induced apoptosis is observed in the presence of a structurally related control compound that only weakly binds to XIAP, demonstrating the specificity of the sensitization effect of XIAP inhibitors. Importantly also in primary CLL samples, XIAP inhibitors act in concert with TRAIL to trigger apoptosis in 18 of 27 cases (67%). Analysis of combination index reveals that this interaction of XIAP inhibitor and TRAIL is highly synergistic. Mechanistic studies in primary CLL cells show that the addition of XIAP inhibitor profoundly enhances TRAIL-induced cleavage of caspase-3 into active fragments and significantly increases caspase-3 enzymatic activity upon treatment with TRAIL. The broad range caspase inhibitor zVAD.fmk completely blocks apoptosis in response to combination treatment with XIAP inhibitor and TRAIL, demonstrating that apoptosis occurs in a caspase-dependent manner. Importantly, the cooperative interaction of XIAP inhibitor and TRAIL is even evident in distinct subgroups of patients with poor prognostic features, including patients with 17p deletion, TP53 mutation, chemotherapy-refractory disease or unmutated VH genes. This suggests that the combination treatment with XIAP inhibitor and TRAIL may present a novel approach to trigger apoptosis in CLL patients that are resistant to other treatment options. Interestingly, we found that cases with unmutated VH genes are significantly more sensitive to XIAP inhibitor- and TRAIL-induced apoptosis compared to VH gene mutated samples. This points to a role of B-cell receptor signaling in the regulation of apoptosis in CLL cells. In conclusion, we demonstrate for the first time that XIAP inhibitors in combination with TRAIL present a new strategy to trigger apoptosis even in resistant forms and poor prognostic subgroups of CLL. These findings have important implications for the development of novel strategies to overcome the intrinsic resistance to apoptosis in CLL. Since IAP inhibitors as well as TRAIL receptor agonists as single agents are currently already under evaluation in early clinical trials, it is feasible that such combination protocols of XIAP inhibitors and TRAIL could be translated into clinical application in CLL. Disclosures: No relevant conflicts of interest to declare.
3

Fakler, Melanie, Sandra Löder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus-Michael Debatin, and Simone Fulda. "Small Molecule XIAP Inhibitors Cooperate with TRAIL to Trigger Apoptosis in Childhood Acute Leukemia Cells and Overcome Bcl-2-Mediated Resistance." Blood 112, no. 11 (November 16, 2008): 857. http://dx.doi.org/10.1182/blood.v112.11.857.857.

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Abstract Children with high risk acute lymphoblastic leukemia (ALL) do not respond well to current treatments. This failure is, at least in part, due to defects in apoptosis programs. Therefore, new strategies are required that counter apoptosis resistance in order to improve the poor prognosis of high risk pediatric acute leukemia. Since XIAP, a member of “Inhibitor of Apoptosis Proteins” (IAPs), is expressed at high levels in acute leukemia and blocks apoptosis at a central point of the apoptotic machinery, XIAP may present a suitable molecular target for therapeutic intervention. Here, we report that neutralizing XIAP by small molecule inhibitors is a novel and effective approach to sensitize childhood acute leukemia cells for TRAIL- or chemotherapy-induced apoptosis. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to induce apoptosis in acute lymphoblastic leukemia cells. Also, XIAP inhibitors act in concert with TRAIL to reduce clonogenic growth of ALL cells demonstrating that they suppress long-term survival. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Intriguingly, XIAP inhibitors overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Thus, XIAP inhibitors combined with TRAIL even break Bcl-2-imposed resistance, a defect in the apoptotic pathway that is common in acute leukemia and associated with poor prognosis. Further, XIAP inhibitors prime ALL cells for apoptosis induced by various anti-leukemic drugs, e.g. cytarabine, doxorubicin, etoposide and 6-mercaptopurine, or by agonistic anti-CD95 antibody. Notably, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In contrast to malignant cells, XIAP inhibitors at equimolar concentrations alone or in combination with TRAIL are non-toxic to normal peripheral blood mononuclear cells despite expression of the apoptosis-inducing TRAIL receptors on the cell surface, pointing to a therapeutic window. Most importantly, XIAP inhibitors significantly reduce leukemic burden in vivo in a mouse model of pediatric ALL engrafted in NOD/SCID mice. Thus, small molecule XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood acute leukemia.
4

Schimmer, Aaron D., Marcela Gronda, Zhiliang Wang, Kate Welsh, Clemencia Pinilla, Michael Andreeff, Wendy D. Schober, et al. "Small-Molecule XIAP Inhibitors Derepress Downstream Effector Caspases and Induce Apoptosis of Leukemia Cell Lines and Patient Samples." Blood 104, no. 11 (November 16, 2004): 759. http://dx.doi.org/10.1182/blood.v104.11.759.759.

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Abstract XIAP is a potent inhibitor of caspases 3, 7, and 9 and its over-expression renders malignant cells resistant to chemotherapy. Through an enzymatic derepression assay, we identified chemical XIAP antagonists, including 1396-12, based on a polyphenylurea pharmacophore (Cancer Cell, 1:25–35;2004). This compound binds and inhibits the caspase 3/7 inhibitory BIR2 domain of XIAP. Given the potential therapeutic utility of IAP inhibitors, we tested this XIAP antagonist in leukemia cell lines and primary patient samples. The XIAP antagonist 1396-12, but not the structurally related control compound, directly induced apoptosis in leukemia cell lines at low micromolar concentrations and sensitized leukemia cells to cytarabine. 1396-12 activated downstream caspases 3/7 prior to the activation of upstream caspases 8 and 9, and independent of Bcl-2 or caspase-8, consistent with the inhibition of the BIR2 domain of XIAP. To evaluate this XIAP antagonist as a potential novel therapy for acute myeloid leukemia (AML), primary AML blasts (n= 27), normal bone marrow mononuclear cells (n =1), or normal mobilized peripheral blood stem cells (PBSC) (n =6) were treated with increasing concentrations of 1396-12. Apoptosis was measured 24 hours after treatment by Annexin V staining. Median LD50 among the AML patient samples tested was 6 μM (range: 2μM to >40μM). The XIAP antagonist 1396-12 induced apoptosis of primary AML samples with a LD50 ≥ 10μM in 16 of 27 (60%) samples and with a LD50 >40μM in 7 of 27 (26%) samples. In contrast, 1396-12 was less toxic to the normal PBSC or marrow with a LD50>40μM in all normal samples tested. As a comparison, the inactive control compound was not toxic to any of the AML or normal samples at concentrations up to 40μM. In addition to the short-term cytotoxicity assays, the effects of 1396-12 on AML and normal samples were evaluated in colony formation assays. The XIAP antagonist inhibited clonogenic survival in 4 AML samples tested with a mean LD50 of 4 ± 0.8μM. Treatment with 1396-12 also reduced colony formation by 2 normal PBSC samples with LD50’s of 8.5 ± 0.3μM and 5.6 ± 0.4μM. In the normal PBSC samples, both BFU-E and CFU-GM lineages were equally reduced after treatment with the XIAP antagonist. Treatment with the control compound did not reduce colony growth in the AML or normal samples. Among the primary AML samples, response to the XIAP inhibitors correlated with XIAP protein levels. Low to absent levels of XIAP were associated with a higher probability of resistance to treatment with XIAP inhibitors (p =0.04, by logistic regression analysis). In conclusion, polyphenylurea-based XIAP antagonists directly induce apoptosis in leukemia cells and patient samples at low micromolar concentrations through a mechanism of action distinct from conventional chemotherapeutic agents. These antagonists can be used as biological tools to understand the role of IAPs in normal and malignant hematopoietic cells. They may also serve as lead compounds for the development of useful therapies for the treatment of leukemia and other malignancies, but their potential hematologic toxicity will have to be carefully evaluated in phase I clinical trials.
5

Schimmer, Aaron D., and Shadi Dalili. "Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy." Hematology 2005, no. 1 (January 1, 2005): 215–19. http://dx.doi.org/10.1182/asheducation-2005.1.215.

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The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
6

Schimmer, Aaron D., and Shadi Dalili. "Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy." Hematology 2005, no. 1 (January 1, 2005): 215–19. http://dx.doi.org/10.1182/asheducation.v2005.1.215.215.

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Abstract The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
7

Fakler, Melanie, Sandra Loeder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus-Michael Debatin, and Simone Fulda. "Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2–mediated resistance." Blood 113, no. 8 (February 19, 2009): 1710–22. http://dx.doi.org/10.1182/blood-2007-09-114314.

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Abstract Defects in apoptosis contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), calling for novel strategies that counter apoptosis resistance. Here, we demonstrate for the first time that small molecule inhibitors of the antiapoptotic protein XIAP cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to trigger apoptosis and to inhibit clonogenic survival of acute leukemia cells, whereas they do not affect viability of normal peripheral blood lymphocytes, suggesting some tumor selectivity. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential, and cytochrome c release in a caspase-dependent manner, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Of note, XIAP inhibitors even overcome Bcl-2–mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In vivo, they significantly reduce leukemic burden in a mouse model of pediatric ALL engrafted in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood ALL.
8

Seno, Saki, Minori Kimura, Yuki Yashiro, Ryutaro Kimura, Kanae Adachi, Aoi Terabayashi, Mio Takahashi та ін. "β-Thujaplicin Enhances TRAIL-Induced Apoptosis via the Dual Effects of XIAP Inhibition and Degradation in NCI-H460 Human Lung Cancer Cells". Medicines 8, № 6 (2 червня 2021): 26. http://dx.doi.org/10.3390/medicines8060026.

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Background: β-thujaplicin, a natural tropolone derivative, has anticancer effects on various cancer cells via apoptosis. However, the apoptosis regulatory proteins involved in this process have yet to be revealed. Methods: Trypan blue staining, a WST-8 assay, and a caspase-3/7 activity assay were used to investigate whether β-thujaplicin sensitizes cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Additionally, western blotting was performed to clarify the effects of β-thujaplicin on X-linked inhibitor of apoptosis protein (XIAP) in NCI-H460 cells and a fluorescence polarization binding assay was used to evaluate the binding-inhibitory activity of β-thujaplicin against XIAP-BIR3. Results: β- and γ-thujaplicins decreased the viability of NCI-H460 cells in a dose-dependent manner; they also sensitized the cells to TRAIL-induced cell growth inhibition and apoptosis. β-thujaplicin significantly potentiated the apoptosis induction effect of TRAIL on NCI-H460 cells, which was accompanied by enhanced caspase-3/7 activity. Interestingly, β-thujaplicin treatment in NCI-H460 cells decreased XIAP levels. Furthermore, β-thujaplicin was able to bind XIAP-BIR3 at the Smac binding site. Conclusions: These findings indicate that β-thujaplicin could enhance TRAIL-induced apoptosis in NCI-H460 cells via XIAP inhibition and degradation. Thus, the tropolone scaffold may be useful for designing novel nonpeptidic small-molecule inhibitors of XIAP and developing new types of anticancer drugs.
9

Cillessen, Saskia A. G. M., John C. Reed, Kate Welsh, Clemencia Pinilla, Richard Houghten, Erik Hooijberg, José Deurhof, et al. "Small-molecule XIAP antagonist restores caspase-9–mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells." Blood 111, no. 1 (January 1, 2008): 369–75. http://dx.doi.org/10.1182/blood-2007-04-085480.

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Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCLs) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including X-linked inhibitor of apoptosis protein (XIAP). XIAP suppresses apoptosis through inhibiting active caspase-3, caspase-7, and caspase-9. In this study, we investigated to see if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of patients with DLBCL. Treatment with this XIAP antagonist resulted in relief of caspase-3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy-refractory and -responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal-center B cells from healthy donors. XIAP antagonist-sensitive samples were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers, suggesting the possibility of predefining patients most likely to benefit from XIAP antagonist therapy.
10

Gaponova, Tatyana, Andrey Misurin, Larisa Mendeleeva, Elena Varlamova, Elena Parovichnikova, and Valeryi Savchenko. "Expression of XIAP in Multiple Myeloma Patients." Blood 112, no. 11 (November 16, 2008): 5118. http://dx.doi.org/10.1182/blood.v112.11.5118.5118.

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Abstract Introduction of novel drugs, in particular, proteasome inhibitors, for the treatment of Multiple Myeloma (MM) patients has significantly improved treatment response and overall survival. One of the effects of proteasome inhibition is down-regulation of the transcription factor NF kB that stimulates the expression of apoptosis inhibitors (IAPs). The expression of IAPs protects cells from the death due to temporary apoptotic stimuli. The overexpression of IAPs is one of the characteristics of malignant cells. A crucial gene of the IAPs family is XIAP which encodes a protein which contains not only the caspase 3 and 7 blocking domain BIR2, but also a unique caspase 9 inhibiting domain BIR3. Therefore, XIAP is able to block both apoptosis pathways: one that depends on external signals and the other that depends on mitochondrial activity. In addition, the RING domain of XIAP has an E3 ubiquitin ligase activity. The aim of our study was to investigate the XIAP expression in MM patients at diagnosis and during chemotherapy, especially with proteosome inhibitors. Our study included 25 primary MM patients; all of them have given informed consent. The median age was 48 years (range 31–62). IgG MM was diagnosed in 22 cases, IgA MM in 1 and Light Chain MM in 2. Initial treatment consisted of 3 cycles of VAD. If CR or PR were not achieved, the treatment was changed to bortezomib 1.3 mg/m2 on days 1,4,8 and 11 and dexamethasone (dex) 40 mg daily on days 1–4 days (4–6 cycles). If CR or PR was attained, Stem Cell mobilization was performed with Cyclophosphamide 6 mg/m2 +G-CSF. Melphalan at 200 mg/m2 was given before auto-SCT. The XIAP expression level was analyzed before therapy (n=25), after VAD (n=12), after bortezomib (n=6) and after auto-SCT (n=4). XIAP expression was evaluated quantitatively by means of RQ-PCR using ABL gene expression for normalization. In primary MM patients the XIAP expression was found in 100%. The meaning of XIAP/ABL*100% varied in the range of 5 to 5382% (median 22%). 24% of MM patients demonstrated XIAP hyperexpression (XIAP/ABL*100%>40%). In the control group of healthy donors the XIAP expression level was not more 13%. We subdivided MM patient into two groups according to XIAP/ABL*100% meaning: I<40%, II>40%. The comparison of M-protein, beta-microglobulin and albumin levels did not reveal any difference between these two groups. However, in group II (with primary XIAP hyperexpression) we observed the decrease of XIAP expression paralled tumor reduction (from more then 40% to 5–20%). On the contrast, in group I the XIAP gene expression increased right after chemotherapy initiation to extremely high levels of 2425%. But, after high dose melphalan and auto-SCT, the XIAP level significantly decreased (22–157%) along with the attainment of CR or very good PR. The level of the XIAP gene expression was also evaluated after the bortezomib treatment. After 4–6 courses of bortesomib + dex in all 6 MM patients CR + PR were achieved, that correlated with XIAP reduction to 8–25%. Conclusion: In MM patients at diagnosis, the level of the XIAP expression is high. The decrease of the XIAP expression correlates with the chemotherapy and proteasome inhibitor treatment efficicacy. XIAP expression comes to the normal values at the time of CR and PR achievement.
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Статті в журналах Дисертації

Дисертації з теми "XIAP inhibitors":

1

Allwood, Daniel Martin. "Discovery and development of novel non-peptidomimetic inhibitors of XIAP." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607657.

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2

Farag, Marc. "Conception assistée par ordinateur d'inhibiteurs de XIAP." Electronic Thesis or Diss., Normandie, 2023. http://www.theses.fr/2023NORMC264.

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Depuis leur découverte, les interactions protéine-protéine (IPPs) sont au centre de nombreux processus biologiques. Ces IPPs peuvent ainsi être la cible de médicaments, soit en mimant une interaction défectueuse ou en inhibant une interaction inadéquate. Parmi les IPPs les plus impliquées dans les pathologies, on trouve les protéines inhibitrices de l’apoptose (IAPs) Ces membres sont considérés comme des régulateurs-clés de la mort cellulaire programmée et au sein des voies de signalisation de la cellule, XIAP, membre de la famille des IAPs est parmi les protéines les plus ciblées actuellement. Son implication dans les cancers et les maladies inflammatoires rares en fait une cible thérapeutique de choix. Les données récentes de la littérature ont soulevé l’importance de la conception de perturbateurs sélectifs de cette protéine pour écarter les effets indésirables graves. De ce fait, il est indispensable de bien connaître les éléments structuraux essentiels associés aux différents domaines de cette protéine, qui la distinguent des autres membres similaires de la famille IAP. Il est également essentiel de connaitre les mécanismes d’interaction dans lesquels XIAP est engagée avec ses partenaires. Les outils de CADD, notamment l’approche Structure Based Drug Design, ainsi que les techniques d’évaluation expérimentale utilisant l’anisotropie de fluorescence (FPA) ou la technologie AlphaScreen® ont été mises en œuvre dans le cadre de ce travail de thèse. Les résultats de ces travaux in silico et in vitro ont conduit à proposer la conception rationnelle de petites molécules sélectives potentiellement perturbateurs des IPPs médiées par XIAP
Since their discovery, protein-protein interactions (PPIs) have been at the heart of many biological processes. These PPIs can be drug targets, either by mimicking a defective interaction or by inhibiting an inadequate interaction. Among the most implicated PPIs in pathologies, we found the Inhibitor Apoptosis Proteins (AAPs). These members are considered as key regulators of programmed cell death and, within the cell signalling pathways, XIAP, a member of the IAP family, is one of the most targeted proteins actually. Its involvement in cancers and rare inflammatory diseases makes it a therapeutic target of choice. Recent data in the literature have highlighted the importance of designing selective disruptors for this protein in order to avoid serious adverse effects. For this reason, it is essential to know the essential structural elements associated with the different domains of this protein, which distinguish it from other similar members of the IAP family. It is also essential to know the interaction mechanisms in which XIAP is involved with its partners. CADD tools, in particular the Structure-based drug design approach, as well as experimental evaluation techniques using fluorescence anisotropy (FPA) or AlphaScreen® technology were used as part of this thesis work. The results of in silico and in vitro work led to rational design proposals of selective small molecules that could potentially disrupt XIAP-mediated PPIs
3

Reiser, Marc [Verfasser]. "Sensitization of pancreatic carcinoma cells for chemotherapy-induced apoptosis using small-molecule inhibitors of X-linked inhibitor of apoptosis protein (XIAP) / Marc Reiser." Ulm : Universität Ulm, 2020. http://d-nb.info/1205001867/34.

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4

Connolly, Kathryn C. "X-linked inhibitor of Apoptosis (XIAP) in colorectal cancer models." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/24478.

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Two methods of XIAP down regulation were considered; transient knock down using antisense (AS) oligonucleotides (OGNs) and stable down regulation by generating short hairpin RNA expression cells. AEG35156 (Aegera Inc), a 2nd generation mixed backbone AS OGN, binds specifically to the sense XIAP and mRNA strand, stimulating its breakdown and preventing translation into protein. A clinical phase I trial of AEG35156 was undertaken in patients with advanced cancer, in Manchester and Edinburgh. The maximum tolerated dose was 96 mg/m2/day of AEG35156, using a 7 day continuous infusion regimen. Dose limiting toxicities were all abnormal laboratory values, reported at higher dose levels (125mg/m2/day and 160mg/m2/day). In laboratory studies, a panel of colorectal cell lines (Colo205, HT29, SW620, HCT15, HCT116) have been characterised according to p53, MLH1 and XIAP status. The HCT116 cell line is mismatch repair deficient (MLH1-) but has a normal functioning p53. It expresses XIAP at levels similar to other members of the cell line panel and is up regulated when compared to normal tissue. A method of transient transfection of XIAP AS (AEG35156) in vitro was developed which achieved 81% down regulation of XIAP mRNA using the AEG35156 compound. Down regulation of XIAP mRNA was also seen with the missense (MS) OGN, AEG35187. Cytotoxicity experiments showed no significant therapeutic benefit of AS over MS. Using short hairpin (shRNA) against XIAP, stably expressed in a parent HCT116 human colon cancer cell line, a series of clones were developed. XIAP mRNA levels were established by RT-PCR, the 4 X (XIAP knockdown) clonal cell lines showing 82-92% reduction in XIAP mRNA when compared to the 4 L (luciferase control) cell lines. Immunoblot analysis showed a 63-89% reduction in XIAP protein in X cell lines compared to L. A colorectal cancer model has been developed using isogenic cell lines which differ only in their XIAP status. The XIAP deficient cell lines show a 2-fold increase in sensitivity to rhTRAIL and 20% increase in sensitivity to radiotherapy. There was a >2-fold increase in sensitivity to paclitaxel and docetaxel. All 8 shRNA cell lines can be established in vivo, the L8 and X23 cell lines showing a similar growth pattern. XIAP knockdown is maintained at the mRNA level for 26 days after implantation, though the down regulation is less than that seen in vitro. However, treatment of X23 and L8 xenografts with docetaxel showed no significant different effect on growth.
5

Liwak-Muir, Urszula. "The Function and Regulation of PDCD4 - A Novel Inhibitor of Selective Translation Initiation." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31375.

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Internal ribosome entry site (IRES)-mediated translation is critical for the cell’s ability to respond to stress. Understanding how RNA binding proteins (IRES trans-acting factors; ITAFs) regulate IRESes is crucial to elucidating the mechanism of alternative translation initiation. Furthermore, determining how these ITAFs are regulated is central to understanding their functions in diseased states. I have identified the tumour suppressor programmed cell death 4 (PDCD4) as a novel ITAF of the XIAP and Bcl-xL IRES elements. I demonstrate that under normal conditions, PDCD4 acts to inhibit translation from these IRES elements by preventing formation of the 48S translation initiation complex. Furthermore, I show that in response to treatment with the pro-survival fibroblast growthfactor-2 (FGF-2), S6 kinase 2 (S6K2) phosphorylates PDCD4 leading to its degradation and the subsequent de-repression of XIAP and Bcl-xL translation. Importantly, I demonstrate the clinical significance of this regulation in glioblastoma multiforme (GBM) tumours where the loss of PDCD4 expression correlates with an increase in Bcl-xL protein and poor patient outcome. Additionally, re-expression of PDCD4 down-regulates Bcl-xL and decreases cell viability, and direct inhibition of Bcl-xL by a small molecule antagonist ABT-737 sensitizes GBM cells to the chemotherapeutic doxorubicin. Finally, I demonstrate that PDCD4 can be regulated at multiple levels. Importantly, I identify the RNA binding protein HuR as a regulator of microRNA (miR) -21 induced silencing of PDCD4. I show that HuR can bind the PDCD4 3'UTR and prevent miR-21 binding, and that a loss of PDCD4 expression following H2O2 treatment is mediated via miR-21. These results provide novel insight into the role of PDCD4 as a tumour suppressor and highlight the importance of ITAFs in cancer progression.
6

Aguilar, Claire. "Caractérisation de la pathologie intestinale associée au déficit en XIAP (X-linked inhibitor of apoptosis protein)." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T072.

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Les mutations du gène codant pour la protéine XIAP (X-Linked Inhibitor of Apoptosis Protein) sont à l’origine du syndrome lymphoprolifératif lié à l’X de type 2 (XLP-2). Il s’agit d’un déficit immunitaire rare caractérisé par une susceptibilité anormale à l’infection par le virus d’Epstein Barr (EBV). De plus, certains patients déficients en XIAP peuvent souffrir d’une pathologie intestinale parfois sévère. XIAP est molécule anti-apoptique qui a aussi été impliquée dans la signalisation et les fonctions de récepteurs de l’immunité innée, les récepteurs NOD1 et NOD2. Mon travail de thèse a eu pour objectif de caractériser cette pathologie intestinale et ses mécanismes physiopathologiques. Pour cela, nous avons étudié une cohorte de patients déficients en XIAP présentant une pathologie inflammatoire intestinale. Nous avons également recherché des mutations de XIAP dans une cohorte d’enfants ayant présenté comme unique signe clinique une pathologie intestinale précoce. Sur 83 patients testés, 3 patients porteurs de mutations de XIAP ont été identifiés. Nous avons ensuite montré que cette pathologie intestinale est très proche sur les plans clinique et histologique de la maladie de Crohn, qui est une des principales affections inflammatoires de l’intestin chez l’adulte. La maladie de Crohn est associée à des facteurs environnementaux et une susceptibilité génétique, dont les polymorphismes dans le gène NOD2 qui représentent le facteur plus important identifié à ce jour. Nous avons ensuite montré que les monocytes des patients déficients en XIAP ont un défaut de production d’IL-8, de MCP-1 et d’IL-10 en réponse à la stimulation de la voie NOD2. Par contre, nous n’avons pas mis en évidence d’excès d’apoptose des cellules épithéliales digestives chez les patients. En revanche, ils présentaient un nombre diminué de leur lymphocytes T innés circulants, Enfin, au cours de cette étude, nous avons identifié pour la première fois des femmes vectrices d’une mutation de XIAP à l’état hétérozygote, ayant développé des manifestations inflammatoires intestinales. Chez ces patientes, l’inactivation du chromosome X, qui normalement est biaisée en faveur de l’allèle sain chez les vectrices asymptomatiques, est de façon inhabituelle biaisée vers l’allèle muté contribuant à une diminution de l’expression de XIAP dans les monocytes et une altération de la voie NOD2. Ce travail a permis de montrer que le déficit en XIAP est responsable d’une forme monogénique de la maladie de Crohn. Nos résultats suggèrent que le défaut d’activation des monocytes par NOD2 est un mécanisme important de la pathogénèse de la maladie. Sur le plan thérapeutique, la greffe de moelle osseuse semble indiquée dans les formes sévères, puisque le principal défaut identifié est une anomalie du compartiment hématopoïétique, et chez deux de nos patients, elle a permis en effet une amélioration franche de la pathologie digestive qui était très sévère
Mutations in the gene encoding for XIAP (X-Linked Inhibitor of Apoptosis Protein) are causing the X-linked lymphoproliferative syndrome type 2 (XLP-2). It is a rare immunodeficiency characterized by an abnormal susceptibility to infection with Epstein Barr virus (EBV). In addition, some XIAP-deficient patients may suffer from an intestinal disease that can be severe. XIAP is an anti-apoptotic molecule which has also been involved in the signaling and the functions of receptors of the innate immunity, NOD1 and NOD2. My thesis work aimed to characterize this intestinal pathology and its pathophysiology. For this, we studied a cohort of known XIAP-deficient patients with inflammatory bowel disease. We also looked for mutations of XIAP in a cohort of children who presented as the only clinical sign an early intestinal pathology. In 83 patients tested, three were identified as carrier of a XIAP mutation. We then showed that this intestinal pathology is clinically and histologically very close to Crohn’s disease, which is a major inflammatory bowel disease in adults. Crohn's disease is associated with environmental factors and genetic susceptibility, including polymorphisms in the NOD2 gene that represent the most important factor identified to date. We then showed that the monocytes from XIAP-deficient patients have a defect in production of IL-8, MCP-1 and IL-10 in response to stimulation of the NOD2 pathway. However, we did not reveal any excess of apoptosis in intestinal epithelial cells from XIAP-deficient patients. On the other hand, they showed a decreased number of their circulating innate T cells. Finally, during this study, we identified for the first time, female carriers of a mutation of XIAP in the heterozygous state, who developed intestinal inflammatory manifestations. In these patients, the inactivation of the X chromosome, which is normally biased toward the healthy allele in asymptomatic vectors, is biased to the unusually mutated allele contributing to a decrease of the expression of XIAP in monocytes and an alteration of the NOD2 pathway. This work showed that XIAP deficiency is responsible for a monogenic form of Crohn's disease. Our results suggest that the lack of monocyte activation by NOD2 is an important mechanism in the pathogenesis of the disease. Therapeutically, the bone marrow transplant seems indicated in severe cases, since the main identified defect is an abnormality of the hematopoietic compartment and in two of our patients, it allowed a clear improvement of the digestive pathology that was very severe
7

Fong, Wai Gin. "The candidate tumour suppressor, XIAP associated factor 1 (XAF1), directly inhibits XIAP activity and induces G1 phase cell cycle arrest." Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/28983.

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X&barbelow;IAP a&barbelow;ssociated f&barbelow;actor 1&barbelow; (XAF1) was initially isolated as novel 34 kDa protein which bound XIAP in a two-hybrid screening. The XAF1A protein consists of 301 a.a. and contains seven potential zinc finger domains. Two alternatively splice variants of XAF1 were later isolated. One isoform (XAF1B) was formed by the removal of a 57 bp exon, which leads to an in-frame deletion of the third zinc finger and the creation of a shorter 32.5 kDa protein. The other splice variant (XAF1C) contains a 154 bp exon insertion, which truncates the sixth and seventh zinc fingers to produce an 18.7 kDa protein. XAF1A and XAF1B, but not XAF1C, bound XIAP in in vitro pull down assays. Northern blot analysis showed at least four distinct sizes of xaf1 mRNA ranging between 3.9 and 7.0 kb, which may indicate other XAF1 isoforms yet to be discovered. Though the possible role of these zinc fingers on the XAF1/XIAP interaction has yet to be determined, recent experiments indicate that XAF1A can block the ability of XIAP to inhibit caspase-3 in vitro. Furthermore, overexpression of XAF1A in HEL299 cells triggered a G1 cell cycle arrest. This G1 arrest coincides with an increase in p21, but not p53. The ability of XAF1 to block XIAP function and induce cell cycle arrest suggests a role for XAF1 in the control of both apoptosis and cell growth. The coding regions of XAF1A, B and C are encoded on a total of 9 exons within a span of 20 kb. The single copy xaf1 gene has been mapped, using FISH analysis, distal to the TP53 gene on 17p13.2. Southern blot analysis of YACS within this region further localizes the xaf1 gene on YAC 746 C 10, which contains the markers D17S1831, D17S796, and D17S1881. These markers are located approximately 3 cM telomeric to the TP53 gene. Since the xaf1 gene is located in a region commonly deleted in numerous types of cancers, this may suggest a tumour suppressor role for XAF1 in cancer. To test this theory, a 60 cell line panel from the NCl was analyzed for xaf1 RNA expression by Taqman and heterozygosity status of markers proximal to xaf1. Taqman analysis indicated that the majority of cell lines expressed little or no xaf1 RNA while xiap levels were relatively high. A PCR study of markers near xaf1 showed significant loss of heterozygosity (LOH) in this region. The loss of xaf1 expression and significant LOH near the xaf1 gene indicate that the down-regulation of XAF1 may be important in the development of the transformed phenotype.
8

Mori, Tomohiko. "Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells." Kyoto University, 2009. http://hdl.handle.net/2433/124345.

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9

Cheema, Tasbir. "Rational Design, Synthesis and Evaluation of Novel Second Mitochondrial-Derived Activators of Caspase (Smac) Mimetics That Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cell Line." Thesis, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/20737.

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Programmed cell death (apoptosis) is the most common mechanism of cell death in eukaryotes. The ability of cancer cells to evade and inhibit apoptosis has become a hallmark feature of cancer. This is accomplished through a family of proteins known as the inhibitor of apoptosis proteins (IAPs). X-Linked inhibitor of apoptosis protein (XIAP) is one of the best characterized IAPs. XIAP suppresses apoptosis by forming complexes with cysteine-aspartic proteases (caspase), through one of its baculovirus IAP repeat (BIR) domains. Its activity is endogenously antagonized by a second mitochondria derived activator of caspase (Smac). The anti-apoptotic behaviour of XIAP and the critical role it plays in the apoptotic program makes the Smac-XIAP interaction an important drug target. To this end, our laboratory is interested in synthesizing biologically related Smac mimetics which can induce apoptosis in a MDA-MB-231 cell line. Efforts have focused on (1) understanding BIR domain binding sites which allow for this interaction, and (2) the design and synthesis of molecules which are much more effective at inducing apoptosis compared to other well known analogues. Through the synthesis and evaluation of various divalent Smac mimetics we have been able to support the hypothesis that the likely binding site on XIAP is the BIR3 domain. As well, through the synthesis of a library of novel compounds, as described in the thesis, we have been able to assess the nature of the linker which joins the two tetrapeptide units. In our effort to understand which domains Smac binds with, various divalent analogues were synthesized containing MeAVPI-linker-IPVMeA (forward-reverse) and MeAVPI-linker-MeAVPI (forward-forward) sequence, which incorporated linkers with varying degrees of flexibility. We hypothesized that the forward-forward divalent mimetics would have decreased activity compared to the peptides synthesized in a forward-reverse fashion. Lastly, information gathered from structure activity relationship (SAR) studies have shown that substituting the lysine (P2) and isoleucine residues (P4) in the AVPI protein can create more potent inducers of apoptosis than its native AVPI sequence. As one of the most potent Smac mimetic that has been previously made known contains an alkyne bridge at P2 and a large hydrophobic moiety at P4, we hypothesized that similar Smac mimetics containing a propargyl glycine residue at P2 and a bulky hydrophobic moiety at P4 will be much more potent in inducing apoptosis.
10

Steen, Håkan. "Novel Interactors of X-linked Inhibitor of Apoptosis Protein : Expression and Effects on Tumor Cell Death." Doctoral thesis, Uppsala University, Neurobiology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8742.

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Programmed cell death, or apoptosis, has during the last decade received a lot of attention due to its involvement in a large number of pathological conditions. Since death is always irreversible, it is important for cells to fully control the initiation and execution of this process. One of many apoptosis-regulatory proteins is XIAP, which blocks the action of caspases, a family of proteases that are important during apoptosis. However, apoptosis inhibitors have to be tightly controlled since too little cell death can lead to the development of tumors and other diseases. This thesis is the result of an aspiration to fully understand the function and regulation of XIAP.

By using the yeast-2-hybrid system, we identified two novel binding partners of XIAP. The first, GPS2, was found to bind XIAP and inhibit its ability to block caspase-activity. In addition, GPS2 induced caspase-mediated cell death in two different tumour cell lines and XIAP inhibited this effect.

The second binding partner, Nulp1, preferentially bound XIAP in the presence of the apoptosis-inducer staurosporine. Nulp1 induced or sensitized cell lines to cell death when overexpressed, but this was not blocked by caspase-inhibitors or XIAP, suggesting a different reason for binding than apoptosis regulation. With the aim to understand the Nulp1-XIAP interaction, we continued to study Nulp1 in vivo and in vitro. We studied three different splice variants of Nulp1 and found that they were regulated by poly-ubiquitination and nuclear shuttling. Also, Nulp1 was expressed in embryonic mice, especially in the cortical plate, hippocampal neurons and cerebellar granular neurons. Expression of Nulp1 decreased with age but was still present in cerebellar deep nuclei and Purkinje cells of adult mice.

To summarize, we have identified GPS2 as an apoptosis-inducing factor and an inhibitor of XIAP in vitro, and Nulp1 as a XIAP-interacting protein during staurosporine-induced apoptosis.

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Частини книг з теми "XIAP inhibitors":

1

Idnani, Tasha Annakin S., and Yong Hsuen Wei Melissa. "Engineering of a Novel Inhibitor of Factor XIa with Better Stability and Inhibitory Efficiency." In IRC-SET 2020, 151–61. Singapore: Springer Singapore, 2021. http://dx.doi.org/10.1007/978-981-15-9472-4_13.

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2

Yang, Wu, James R. Corte, and Joseph M. Luettgen. "RECENT PROGRESS IN FACTOR XI/XIA INHIBITOR DISCOVERY." In 2022 Medicinal Chemistry Reviews, 117–41. Washington, DC: MEDI, Inc. Published by American Chemical Society., 2022. http://dx.doi.org/10.1021/mc-2022-vol57.ch05.

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3

Tey, B. T., K. C. Yap, A. M. Ali, and W. S. Tan. "The X-link inhibitor of apoptosis protein (XIAP) enhances the survivability of C2E7 hybridoma cells under a serum deprived condition." In Animal Cell Technology: Basic & Applied Aspects, 67–72. Dordrecht: Springer Netherlands, 2006. http://dx.doi.org/10.1007/1-4020-4457-7_9.

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4

Fredenburgh, James C., and Jeffrey I. Weitz. "Forthcoming oral factor XIa and factor XIIa inhibitors." In The ESC Textbook of Thrombosis, edited by Raffaele De Caterina, David J. Moliterno, and Steen Dalby Kristensen, 133–40. Oxford University PressOxford, 2023. http://dx.doi.org/10.1093/med/9780192869227.003.0012.

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Abstract Oral anticoagulants are a mainstay for the prevention and treatment of arterial and venous thrombosis. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists for many indications. Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F)-Xa. A new class of DOACs is under development. These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation. Anticoagulants that target FXIa have the potential to be safer than the current DOACs because there is emerging evidence that FXI is essential for thrombosis but mostly dispensable for haemostasis. In addition to the oral inhibitors of FXIa, parenteral inhibitors also are under development. These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI, abelacimab, an antibody that binds FXI and blocks its activation, and osocimab, an FXIa inhibitory antibody. FXII inhibitors, which may be even safer than those that target FXI, are at an earlier stage of development. Focusing on these new agents, this chapter (1) describes the unmet needs in oral anticoagulation therapy, (2) explains why FXI and FXII are promising targets for new oral anticoagulants, (3) reviews the clinical data with the new agents, and (4) provides perspective on the opportunities and challenges for oral FXIa and FXIIa inhibitors.
5

Yim, JH, WG Kim, G. Gong, EY Kim, TY Kim, JH Joon, SJ Hong, WB Kim, and YK Shong. "X-Linked Inhibitor of Apoptosis (XIAP) in Papillary Thyroid Carcinoma." In The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego, P1–534—P1–534. Endocrine Society, 2010. http://dx.doi.org/10.1210/endo-meetings.2010.part1.p11.p1-534.

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Тези доповідей конференцій з теми "XIAP inhibitors":

1

Kawamura, Tatsuro, Hitomi Otaka, Etsu Tashiro, and Masaya Imoto. "Abstract B157: Generation of “Natural Unnatural Product Library” and identification of small molecule XIAP inhibitors." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-b157.

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2

Chessari, Gianni, Ildiko Buck, Elisabetta Chiarparin, James Day, Martyn Frederickson, Keisha Hearn, Tom Heightman, et al. "Abstract 2018: Discovery of potent dual inhibitors of both XIAP and cIAP1 using fragment based drug discovery." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2018.

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3

Vellanki, Sri Harikrishna, Andreas Grabrucker, Stefan Liebau, Adriana Eramo, Veit Braun, Tobias Böckers, Klaus-Michael Debatin та Simone Fulda. "Abstract 3480: XIAP inhibitors prime glioblastoma cells for γ-irradiation-induced apoptosis and circumvent radioresistance of glioblastoma stem cells". У Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-3480.

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4

Tans, G., T. Janssen-Claessen, J. Rosing, and J. H. Griffin. "APPLICATION OF SPECIFIC SERINE PROTEASE INHIBITORS IN ASSAYS FOR ACTIVATED CONTACT FACTORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643301.

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We developed amidolytic assays to determine human Factor Xlla, Factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic substrates pro-phe-arg-pNA (S2302 or chromozym PK), glu-pro-arg-pNA (S2366), ile-glu-(piperidyl)-gly-arg-pNA (S2337), and ile-glu-gly-arg-pNA (S2222) were tested for their suitability as substrates in these assays. 8-Factor Xlla, Factor XIa and plasma kallikrein each exhibit considerable activity towards a number of these substrates. This precludes direct quantitation of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors were tested on their ability to selectively inhibit those contact factors that may interfere with the factor tested for. Soybean trypsin inhibitor efficiently inhibits kallikrein, inhibits Factor XIa at moderate concentrations, but did not affect the amidolytic activity of Factor Xlla. Therefore, this inhibitor can be used to abolish a kallikrein and Factor XIa contribution in a Factor Xlla assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethylketones. D-phe-pro-arg-CH 2 Cl was moderately active against contact factors (k - 2271 M-ls-1 at pH 8.3) but showed no differences in specif ity. D-phe-phe-arg-CH2 Cl was a very efficient inhibitor of kallikrein (k = 118,000 M-ls-1 at pH 8.3) whereas it slowly inhibited Factor Xlla (k = 1389 M-ls-1) and Factor XIa (k = 110 M-ls-1). Also dansyl-glu-gly-arg-CH2Cl was more reactive towards kallikrein (k 15,662 M-ls-1) than towards Factor Xlla (k = 462 M-ls-1) and Factor XIa (k = 63 M-ls-1). Since phe-phe-arg-CH2Cl is highly specific for kallikrein it can be used in a Factor XIa assay to selectively inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for Factor Xlla, Factor XIa and kallikrein in mixtures of contact activation factors.
5

Ahmed, Maqbool, Azhar R. Hussain, Shaham Beg, Saravanan Thangavel, Rafia Begum, Dahish Ajarim, Fouad Al-Dayel, Abdul Khalid Siraj K. Siraj, and Khawla S. Al-kuraya. "Abstract 4405: Over-expression of PARP is associated with an aggressive phenotype and can be synergistically targeted using combination of PARP and XIAP inhibitors in breast cancer." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-4405.

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6

Fakler, Melanie, Sandra Löder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus-Michael Debatin, and Simone Fulda. "Abstract 2911: Small molecule XIAP inhibitors sensitize acute leukemia cells for TRAIL- or chemotherapy-induced apoptosis, overcome Bcl-2-mediated resistance and reduce leukemic burden in vivo in NOD/SCID mice." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2911.

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7

Fakler, Melanie, Sandra Loeder, Meike Vogler, Katja Schneider, Irmela Jeremias, Klaus‐Michael Debatin, and Simone Fulda. "Abstract PR-8: XIAP inhibitors prime acute leukemia cells for TRAIL‐ or chemotherapy‐induced apoptosis, bypass Bcl‐2‐imposed resistance and exert antileukemic activity in a NOD/SCID mouse model of pediatric acute leukemia." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 15-19, 2009; Boston, MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/1535-7163.targ-09-pr-8.

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8

Walsh, P. N., D. Sinha, F. Kueppers, F. S. Seaman, and K. B. Blanketein. "THE REGULATION OF FACTOR XIa ACTIVITY BY PLATELETS AND ALPHA-1-PROTEASE INHIBITOR." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642805.

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Since activated platelets bind factor XI (FXI), FXIa and high molecular weight kininogen (HMWK), promote the proteolytic activation of FXI, release an inhibitor of FXIa, and may protect FXIa from inactivation by plasma protease inhibitors, we have studied the complex interrelationships between platelets, FXIa, alpha-l-protease inhibitor (α1PI) and F-IX activation. Purified FXIa was incubated in the presence or absence of thrombin-treated gel-filtered platelets (GFP) or a platelet releasate and FXIa activity assayed by the release of a H-labeled activation peptide from H-FIX. Our results confirm the report of Soons et al (Blood 68:140, 1986) that platelets secrete an inhibitor of FXIa (PXIaI). The presence of intact GFP partially protected FXIa from inactivation by the PXIaI. The presence of GFP also partially protected FXIa from inactivation in the presence of both α1PI and the PXIaI. Purified HMWK had no effect on FXIa inactivation by α1PI or by the PXIaI. Both platelet-bound FXIa and unbound FXIa in the presence of thrombin-activated platelets were protected from inactivation by α1PI. Thrombin-treated GFP had no effect on the capacity of cxjPI to inactivate trypsin or elastase. Thus the protection of FXIa from inactivation by α1PI and/or the PXIaI did not arise from a) the binding of FXIa to platelets, b) the presence of HMWK, or c) the inactivation of α1PI by platelets. When 125I-labeled FXIa was incubated with α1PI and examined by autoradiography of SDS polyacrylamide gels a complex (Mr 85,000) was observed between the active-site-containing FXIa light chain (Mr 30,000) and α1PI (Mr 54,000). The formation of this complex was inhibited in the presence of activated platelets or platelet releaseates, but was not affected by HMWK. These results support the hypothesis that platelets can regulate FXIa catalyzed F-IX activation by secreting an inhibitor of FXIa that may act primarily outside the platelet microenvironment and by protecting FXIa from inhibition, thereby localizing F-IX activation to the platelet plug.
9

Li, Fengzhi, Shousong Cao, and Xiang Ling. "Abstract 3446: FL118, a survivin/Mcl-1/XIAP/cIAP2-selective inhibitor, effectively inhibits human mesothelioma xenograft growth in animal models." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3446.

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10

Hongo, Fumiya, Natsuki Takaha, Yasunori Kimura, Terukazu Nakamura, kazuya Mikami, and Tsuneharu Miki. "Abstract 4493: Serum X-linked inhibitor of apoptosis protein (XIAP) predictive recurrence of renal cell carcinoma." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-4493.

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Звіти організацій з теми "XIAP inhibitors":

1

Lu, Yipin. Discovery and Test of Small Molecule Inhibitions of XIAP as Potential Novel Therapy for the Treatment of Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, April 2005. http://dx.doi.org/10.21236/ada435631.

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