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Small-molecule factor B inhibitor for the treatment of complement-mediated diseases

Schubart Wellensiek, Anna, Anderson, Karen, Mainolfi, Nello, Sellner, Holger, ehara, Takeru, Adams, Christopher, Mac Sweeney, Aengus, Liao, Sha-Mei, Crawley, Maura, Littlewood-Evans, Amanda, Sarret, Sophie, Wieczorek, Grazyna, Perrot, Ludovic, Dubost, Valerie, Flandre, Thierry, Zhang, Yuzhou, Smith, Richard, Risitano, Antonio, Karki, Rajeshri, Zhang, Chun, Valeur, Eric, Sirockin, Finton, Gerhartz, Bernd, Erbel, Paulus, Aubin, Nicola, Smith, Thomas, Cumin, Frederic, Argikar, Upendra, Haraldsson, Boerje, Mogi, Muneto, Sedrani, Richard, Wiesmann, Christian, Jaffee, Bruce, Maibaum, Juergen Klaus, Flohr, Stefanie and Harrison, Richard (2019) Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proceedings of the National Academy of Sciences of the United States of America, 116 (16). pp. 7926-7931. ISSN 10916490


Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number of diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead to complement-driven nephropathies. Here we describe the discovery of a highly potent, reversible, and selective small-molecule inhibitor of factor B, a serine protease that drives the central amplification loop of the AP. Oral administration of the inhibitor prevents KRN-induced arthritis in mice and is effective upon prophylactic and therapeutic dosing in an experimental model of membranous nephropathy in rats. In addition, inhibition of factor B prevents complement activation in sera from C3 glomerulopathy patients and the hemolysis of human PNH erythrocytes. These data demonstrate the potential therapeutic value of using a factor B inhibitor for systemic treatment of complement-mediated diseases and provide a basis for its clinical development.

Item Type: Article
Keywords: Alternative pathway Complement Drug discovery Factor B Nephropathy
Date Deposited: 04 Jun 2019 00:45
Last Modified: 04 Jun 2019 00:45