Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist

Erickson‐Miller, Connie L.; Delorme, Evelyne; Tian, Shin-Shay; Hopson, Christopher B.; Stark, Kenneth; Giampa, Leslie; Valoret, Elizabeth I.; Duffy, Kevin J.; Luengo, Juan L.; Rosen, Jon; Miller, Stephen G.; Dillon, Susan B.; Lamb, Peter

doi:10.1016/j.exphem.2004.09.006

Cited by 181 publications

(144 citation statements)

References 30 publications

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“…The selectivity of eltrombopag for the TPO-receptor rather than other growth factor receptors was demonstrated by assays measuring STAT activation or reporter gene expression in various transfected and non-transfected cell lines. The assays confirmed the ability of eltrombopag to activate signalling in cells expressing the TPO receptor but showed that it had no effect on cells expressing only interferon-γ, granulocyte macrophage-colony stimulating factor (GM-CSF), G-CSF, erythropoietin or interleukin-3 receptors [36]. The fact that eltrombopag lacks activity against cells expressing growth factor receptors other than TPO, even those acting through the JAK/STAT signalling pathway, suggests that the activation of JAK/STAT by eltrombopag is due to the specific activation of the TPO receptor [37].…”

Section: Eltrombopagmentioning

confidence: 86%

“…The response of normal human TPO receptors has been elucidated by measuring growth and differentiation of human bone marrow in vitro. These studies demonstrated human and chimpanzee-specific stimulation of TPOreceptor-expressing cells via activation of STAT5, with no eltrombopag-induced STAT activation observed in other species tested, including cynomolgus macaques, rhesus monkeys, pigs, dogs, ferrets, rabbits, rats and mice [36]. The selectivity of eltrombopag for the TPO-receptor rather than other growth factor receptors was demonstrated by assays measuring STAT activation or reporter gene expression in various transfected and non-transfected cell lines.…”

Section: Eltrombopagmentioning

confidence: 89%

“…Eltrombopag displays receptor-specific and species-specific binding In preclinical studies, eltrombopag has been shown to stimulate human megakaryocyte differentiation and proliferation in a dose-dependent manner, via stimulation of the TPO receptor [36].…”

Section: Eltrombopagmentioning

confidence: 99%

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Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Kühne

Imbach

2010

Ann Hematol

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Immune thrombocytopenia (ITP) is characterised by a transient or persistent decrease in platelets accompanied by an increased risk of bleeding, which can have a significant negative impact on patients' health-related quality of life. The condition has long been associated with an increased rate of immune-mediated platelet destruction, and traditional treatments have targeted the reduction in platelet destruction; however, some interventional drugs are limited by transient efficacy and side effects. Recent advances in our understanding of ITP pathogenesis have highlighted the role of impaired platelet production, which has led to the advent of a new generation of thrombopoietin (TPO)-receptor agonist therapies, including eltrombopag and romiplostim. The oral, non-peptide TPO-receptor agonist eltrombopag has shown considerable promise in both preclinical and clinical trials. Eltrombopag has a unique mechanism of action and binds to a transmembrane region of the TPO receptor that is distant from the TPO binding site. As such, eltrombopag may confer synergistic effects with endogenous TPO rather than competing for binding. Eltrombopag also induces activation of the TPO receptor and downstream signalling in a distinct manner to TPO and does not have a significant impact on platelet function. Clinical evidence demonstrates that eltrombopag produces a rapid and sustainable increase in platelet counts that significantly reduces bleeding and is well tolerated in patients with ITP. Eltrombopag therefore represents an important addition to the therapeutic armamentarium for ITP.

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Section: Eltrombopagmentioning

confidence: 86%

Section: Eltrombopagmentioning

confidence: 89%

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Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Kühne

Imbach

2010

Ann Hematol

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“…Newer TPO receptor agonists have no sequence homology with the native molecule and are not expected to provoke crossreactive antibodies. Results from recent trials with these agents provide in vivo evidence that boosting platelet production is an effective therapeutic strategy [59,60,64,65]. Four TPO receptor agonists are currently being evaluated in patients with ITP-romiplostim (Amgen, Thousand Oaks, CA), eltrombopag or SB-497115 (GlaxoSmithKline, Collegeville, PA), AKR-501 (MGI Pharma, Bloomington, MN), and LGD-4665 (Ligand Pharmaceuticals, San Diego, CA).…”

Section: Emerging Therapies Target Platelet Productionmentioning

confidence: 99%

Chronic Idiopathic Thrombocytopenic Purpura: Mechanisms of Pathogenesis

Gernsheimer

2009

The Oncologist

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The mechanism of idiopathic (autoimmune) thrombocytopenic purpura (ITP) has historically been attributed to platelet autoantibody production and the resultant platelet destruction. More recent evidence suggests a multifactorial pathogenesis. A complex picture of the immune processes involved in autoimmunity has emerged over the last decade with the identification and characterization of immunoregulatory elements (receptors, cytokines, and other signaling molecules) and cell trafficking patterns. An understanding of the interplay of cellular and humoral immune responses in the breakdown of self-tolerance has brought to light unrecognized mechanisms of the autoimmune destruction of platelets in ITP and potential targets for future therapeutic advances. The failure of the bone marrow to maximally increase platelet production also appears to play an important role in the thrombocytopenia of ITP. Treatment strategies targeting the thrombopoietin receptor to increase platelet production are a promising new approach to the management of ITP.

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“…[8,9] Obwohl die Inhibierung von Protein-Protein-Interaktionen (PPIs) mittels kleiner Moleküle lange Zeit als die ultimative Herausforderung in der Wirkstoffentwicklung galt, wurden nur sehr wenige Beispiele für solche PPI-Inhibitoren beschrieben. [10][11][12][13] Demgegenüber gibt es klare mechanistischkonzeptionelle Argumente dafür, dass PPI-Stabilisatoren großes Potential haben kçnnten. [14] LFA-1-Aktivatoren wären ein vielversprechender Ansatz für die Behandlung einer seltenen Erbkrankheit, bekannt als Leukozytenadhäsi-onsdeffizienz (LAD), oder als mçgliche Verstärker in der Tumorimmuntherapie.…”

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Identifizierung und Strukturbestimmung eines niedermolekularen Aktivators der LFA‐1/ICAM‐1‐Bindung

et al. 2014

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Das Integrin LFA-1 (leukozytenfunktionsassoziertes Antigen 1) ist ein heterodimerer Immunrezeptor, der ubiquitär auf Leukozyten exprimiert wird. Die Bindung von LFA-1 mit dem interzellulären Adhäsionsmolekül 1 (ICAM-1) ist entscheidend für das Immunsystem, um eine frühe zellvermittelte Immunantwort auszulçsen. [1][2][3] Auf diese Weise erkennen T-Zellen antigenpräsentierende Zellen. Die Bindungsachse zwischen LFA-1 und ICAM-1 wurde aus diesem Grund bereits früher als mçglicher Ansatzpunkt für die Medikamententwicklung beschrieben. [4][5][6][7] Allerdings stellt die Konformationsänderung von niedrig affinen zu hochaffinen Zuständen, die mit der Bindung von LFA-1 an ICAM-1 einhergeht, eine erhebliche Hürde für die Konstruktion von LFA-1-Inhibitoren dar. [8,9] Obwohl die Inhibierung von Protein-Protein-Interaktionen (PPIs) mittels kleiner Moleküle lange Zeit als die ultimative Herausforderung in der Wirkstoffentwicklung galt, wurden nur sehr wenige Beispiele für solche PPI-Inhibitoren beschrieben. [10][11][12][13] Demgegenüber gibt es klare mechanistischkonzeptionelle Argumente dafür, dass PPI-Stabilisatoren großes Potential haben kçnnten. [14] LFA-1-Aktivatoren wären ein vielversprechender Ansatz für die Behandlung einer seltenen Erbkrankheit, bekannt als Leukozytenadhäsi-onsdeffizienz (LAD), oder als mçgliche Verstärker in der Tumorimmuntherapie. [15,16] Ein scheinbarer Aktivator für LFA-1 wurde bisher beschrieben, [17] allerdings ergab die nähere Untersuchung, dass diese Substanz im Endeffekt als Inhibitor wirkt, da sie die transendotheliäre Migration von Leukozyten blockiert. Schema 1. Das Konzept zum Screenen von AIDA-markierten OBOC-Bibliotheken: Der 1,3-Diaryl-substituierte Indazolfarbstoff AIDA wird bei der kombinatorischen Festphasensynthese von Substanzbibliotheken als erster Baustein eingeführt. Die einzelnen Verbindungen der Bibliothek aus 1,4-Diazepan-2-onen sind über einen Diaminopropan-Spacer an den Farbstoff gebunden. Nach Inkubieren der Beads mit fluoreszenzmarkierten Zielproteinen wird CONA [18] verwendet, um jene Beads mit gebundenem Protein nachzuweisen. Nach Isolierung der Hits dient AIDA als Marker, um die massenspektrometrische Substanzdekodierung zu vereinfachen, und als Reporter für einen sekundären Bindungsassay. Letzerer ermçglicht die Messung der Affinität von AIDAmarkierten Hit-Verbindungen mit unmarkiertem Zielprotein in homogener Lçsung.[

show abstract

Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist

Cited by 181 publications

References 30 publications

Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Eltrombopag: an update on the novel, non-peptide thrombopoietin receptor agonist for the treatment of immune thrombocytopenia

Chronic Idiopathic Thrombocytopenic Purpura: Mechanisms of Pathogenesis

Identifizierung und Strukturbestimmung eines niedermolekularen Aktivators der LFA‐1/ICAM‐1‐Bindung

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