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.
Small-molecule factor B inhibitor for the treatment of complement-mediated diseases / Schubart, A.; Anderson, K.; Mainolfi, N.; Sellner, H.; Ehara, T.; Adams, C. M.; Sweeney, A. M.; Liao, S. -M.; Crowley, M.; Littlewood-Evans, A.; Sarret, S.; Wieczorek, G.; Perrot, L.; Dubost, V.; Flandre, T.; Zhang, Y.; Smith, R. J. H.; Risitano, A. M.; Karki, R. G.; Zhang, C.; Valeur, E.; Sirockin, F.; Gerhartz, B.; Erbel, P.; Hughes, N.; Smith, T. M.; Cumin, F.; Argikar, U. A.; Haraldsson, B.; Mogi, M.; Sedrani, R.; Wiesmann, C.; Jaffee, B.; Maibaum, J.; Flohr, S.; Harrison, R.; Eder, J.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 116:16(2019), pp. 7926-7931. [10.1073/pnas.1820892116]
Small-molecule factor B inhibitor for the treatment of complement-mediated diseases
Risitano A. M.;
2019
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
