title: Novel immunosuppression: R348, a JAK3- and Syk-inhibitor attenuates acute cardiac allograft rejection.
abstract: BACKGROUND
  Janus kinase (JAK)3 is crucial for signal transduction downstream of various cytokine receptors in immune cells. This is the first report on the novel JAK3 inhibitor R348.
  
  
  METHODS
  (1) Detailed pharmacokinetic data were obtained in rats; (2) multiple in vitro enzyme inhibition assays were performed to characterize the drug; (3) prevention of acute rejection was investigated in animals treated with different doses of R348 or rapamycin for 5 days; and (4) cardiac allograft survival after a 10-day treatment period was studied for various regimens of R348, tacrolimus, or rapamycin; combination indices were calculated to evaluate drug interactions.
  
  
  RESULTS
  (1) Plasma levels of R348's active metabolite R333 sustained high for 8 hr or more, depending on the dose. (2) In vitro enzyme assays showed potent inhibition of JAK3- and Syk-dependent pathways. (3) R348 40 mg/kg preserved graft function, significantly reduced graft infiltration, and decreased histologic ISHLT rejection scores on postoperative day 5. Results were similar to those of rapamycin 3 mg/kg. Likewise, both drugs significantly reduced the cellular Th1 and Th2 immune responses, as determined by enzyme-linked immunosorbent assays. Intragraft inflammatory cytokine upregulation was similarly suppressed by R348 and rapamycin. R348 10 mg/kg was subtherapeutic. (4) Allograft survival was similar for R348 20 and 40 mg/kg, which was comparable with therapeutically dosed tacrolimus or rapamycin. In combination regimens, R348 demonstrated highly beneficial synergistic interactions with tacrolimus.
  
  
  CONCLUSIONS
  R348 is a promising novel JAK3/Syk-inhibitor with favorable pharmacokinetics and biological activity. It effectively diminishes acute cardiac allograft rejection and is suitable for combination regimens with tacrolimus.
authors: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Tobias
authors: T
authors: Deuse
authors: Jeffrey B
authors: JB
authors: Velotta
authors: Grant
authors: G
authors: Hoyt
authors: Johannes A
authors: JA
authors: Govaert
authors: Vanessa
authors: V
authors: Taylor
authors: Esteban
authors: E
authors: Masuda
authors: Ellen
authors: E
authors: Herlaar
authors: Gary
authors: G
authors: Park
authors: David
authors: D
authors: Carroll
authors: Marc P
authors: MP
authors: Pelletier
authors: Robert C
authors: RC
authors: Robbins
authors: Sonja
authors: S
authors: Schrepfer
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000627:therapeutic use; D000072377:Syk Kinase
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3; D000072377:Syk Kinase; C000606898:Syk protein, rat; D020123:Sirolimus