Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Schubart Wellensiek, Anna and Anderson, Karen and Mainolfi, Nello and Sellner, Holger and ehara, Takeru and Adams, Christopher and Mac Sweeney, Aengus and Liao, Sha-Mei and Crawley, Maura and Littlewood-Evans, Amanda and Sarret, Sophie and Wieczorek, Grazyna and Perrot, Ludovic and Dubost, Valerie and Flandre, Thierry and Zhang, Yuzhou and Smith, Richard and Risitano, Antonio and Karki, Rajeshri and Zhang, Chun and Valeur, Eric and Sirockin, Finton and Gerhartz, Bernd and Erbel, Paulus and Aubin, Nicola and Smith, Thomas and Cumin, Frederic and Argikar, Upendra and Haraldsson, Boerje and Mogi, Muneto and Sedrani, Richard and Wiesmann, Christian and Jaffee, Bruce and Maibaum, Juergen Klaus and 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


Email Alerts

Register with OAK to receive email alerts for saved searches.