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

Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931. doi: 10.1073/pnas.1820892116. Epub 2019 Mar 29.


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.

Keywords: alternative pathway; complement; drug discovery; factor B; nephropathy.

MeSH terms

  • Animals
  • Complement Factor B / antagonists & inhibitors*
  • Complement Pathway, Alternative / drug effects*
  • Disease Models, Animal
  • Drug Discovery / methods*
  • Glomerulonephritis, Membranous / physiopathology
  • Humans
  • Immunologic Factors / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Rats, Sprague-Dawley


  • Immunologic Factors
  • Complement Factor B

Associated data

  • PDB/6QSW
  • PDB/6QSX
  • PDB/6QSV