Target Validation Information
Target ID T76024
Target Name C1 esterase
Target Type
Successful
Drug Potency against Target Cinryze Drug Info IC50 = 1.053 U/mL
Rhucin Drug Info IC50 = 1.053 U/mL
Action against Disease Model Romiplostim AMG 531 stimulates murine megakaryopoiesis in vitro by binding to Mpl in the same manner as TPO, via activation of signaling pathways including tyrosine phosphorylation of Mpl, Janus kinase (JAK) 2, and signal transducer and activators of transcription (STAT) 5 14. In vitro studies have also demonstrated that AMG 531 is a potent stimulant of megakaryopoiesis. AMG 531 exerteda dose-dependent effect on the growth of megakaryocytic colony-forming units (CFU-Meg) from murine marrow cells. AMG 531 also stimulated the proliferation of BaF3 cells that expressed h uMan Mpl in adose-dependent fashion, but had no effect on parental BaF3 cells that did not express Mpl. In vitro studies also showed that AMG 531 competes effectively with TPO for binding to h uMan Mpl on normal platelets. [552631] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. Byits C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency ofC1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with theexisting plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent. [552631]
References
Ref 552631AMG 531: an investigational thrombopoiesis-stimulating peptibody. Pediatr Blood Cancer. 2006 Oct 15;47(5 Suppl):723-5.

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