Dual targeting of Bruton's tyrosine kinase and Janus kinase 3 with rationally designed inhibitors prevents graft-versus-host disease (GVHD) in a murine allogeneic bone marrow transplantation model.

Abstract

The purpose of the present study was to evaluate the effectiveness of targeting Bruton's tyrosine kinase (BTK) with a specific BTK inhibitor, alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13), for prevention of acute fatal graft-versus-host disease (GVHD) in a murine model of allogeneic bone marrow transplantation (BMT). Vehicle-treated control C57BL/6 mice receiving bone marrow/splenocyte grafts from allogeneic BALB/c donors developed severe multi-organ acute GVHD and died after a median survival time (MST) of 40 d. LFM-A13 treatment (25 mg/kg/d) significantly prolonged the MST of the BMT recipients to 47 d. The probability of survival at 2 months after BMT was 2 +/- 2% for vehicle-treated control mice and 22 +/- 6% for mice treated with LFM-A13 (P = 0.0008). Notably, the combination regimen of LFM-A13 plus the standard anti-GVHD drug methotrexate (MTX) (10 mg/m(2)/d) was more effective than LFM-A13 alone, while the combination regimen of LFM-A13 plus the novel anti-GVHD drug JANEX-1 (60 mg/kg/d), targeting Janus kinase 3, was more effective than LFM-A13, JANEX-1 or MTX alone. More than 70% of recipients receiving this most effective GVHD prophylaxis (LFM-A13 + JANEX-1) remained alive throughout the 80-d observation period with an MST of >80 d. Taken together, these results indicate that targeting BTK with the chemical inhibitor LFM-A13 may attenuate the severity of GVHD, especially when it is combined with other anti-GVHD drugs, such as MTX and JANEX-1.

• Authors: Marina Cetkovic-Cvrlje, Fatih M Uckun
• Journal: British journal of haematology (Br J Haematol) Vol. 126 Issue 6 Pg. 821-7 (Sep 2004) ISSN: 0007-1048 [Print] England
• PMID: 15352986 (Publication Type: Journal Article)

Chemical References

• Amides
• Enzyme Inhibitors
• Immunosuppressive Agents
• LFM A13
• Nitriles
• Quinazolines
• WHI P131
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Btk protein, mouse
• Jak3 protein, mouse
• Janus Kinase 3
• Methotrexate

Topics

• Acute Disease
• Agammaglobulinaemia Tyrosine Kinase
• Amides (therapeutic use)
• Animals
• Bone Marrow Transplantation
• Drug Therapy, Combination
• Enzyme Inhibitors (therapeutic use)
• Graft vs Host Disease (prevention & control)
• Immunosuppressive Agents (therapeutic use)
• Janus Kinase 3
• Male
• Methotrexate (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Nitriles (therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinazolines (therapeutic use)
• Survival Rate
• Treatment Outcome