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Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.
Schubart, Anna; Anderson, Karen; Mainolfi, Nello; Sellner, Holger; Ehara, Takeru; Adams, Christopher M; Mac Sweeney, Aengus; Liao, Sha-Mei; Crowley, Maura; Littlewood-Evans, Amanda; Sarret, Sophie; Wieczorek, Grazyna; Perrot, Ludovic; Dubost, Valérie; Flandre, Thierry; Zhang, Yuzhou; Smith, Richard J H; Risitano, Antonio M; Karki, Rajeshri G; Zhang, Chun; Valeur, Eric; Sirockin, Finton; Gerhartz, Bernd; Erbel, Paulus; Hughes, Nicola; Smith, Thomas M; Cumin, Frederic; Argikar, Upendra A; Haraldsson, Börje; Mogi, Muneto; Sedrani, Richard; Wiesmann, Christian; Jaffee, Bruce; Maibaum, Jürgen; Flohr, Stefanie; Harrison, Richard; Eder, Jörg.
Affiliation
  • Schubart A; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Anderson K; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Mainolfi N; Ophthalmology, Biogen, Cambridge, MA 02142.
  • Sellner H; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Ehara T; Kymera Therapeutics, Cambridge, MA 02139.
  • Adams CM; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Mac Sweeney A; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Liao SM; PeptiDream Inc., Kawasaki-shi, 210-0821 Kanagawa, Japan.
  • Crowley M; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Littlewood-Evans A; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Sarret S; Drug Discovery Biology, Idorsia Pharmaceuticals Ltd., 4123 Allschwil, Switzerland.
  • Wieczorek G; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Perrot L; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Dubost V; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Flandre T; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Zhang Y; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Smith RJH; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Risitano AM; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Karki RG; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Zhang C; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
  • Valeur E; Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
  • Sirockin F; Department of Clinical Medicine and Surgery, Bone Marrow Transplantation Program, Federico II University, 80138 Naples, Italy.
  • Gerhartz B; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Erbel P; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Hughes N; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Smith TM; Medicinal Chemistry, Cardiovascular, Renal & Metabolism, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, 431 83 Mölndal, Sweden.
  • Cumin F; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Argikar UA; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Haraldsson B; Protein Sciences, Abcam PLC, CB4 0GZ Cambridge, United Kingdom.
  • Mogi M; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Sedrani R; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Wiesmann C; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Jaffee B; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Maibaum J; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Flohr S; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
  • Harrison R; Novartis Institutes for BioMedical Research, Cambridge, MA 02139.
  • Eder J; Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.
Proc Natl Acad Sci U S A ; 116(16): 7926-7931, 2019 04 16.
Article in En | MEDLINE | ID: mdl-30926668
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Complement Factor B / Complement Pathway, Alternative / Drug Discovery / Immunologic Factors Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Proc Natl Acad Sci U S A Year: 2019 Type: Article Affiliation country: Switzerland
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Complement Factor B / Complement Pathway, Alternative / Drug Discovery / Immunologic Factors Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Proc Natl Acad Sci U S A Year: 2019 Type: Article Affiliation country: Switzerland