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

British Journal of Haematology
Marina Cetkovic-Cvrlje, Fatih M Uckun

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 ...Continue Reading

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Citations

Jun 26, 2012·Cellular & Molecular Immunology·Marina Cetkovic-CvrljeKetaki Ghate
Mar 16, 2013·OncoTargets and Therapy·Osmond J D'Cruz, Fatih M Uckun
Feb 27, 2008·International Reviews of Immunology·Fatih M Uckun
Feb 28, 2015·Journal of Immunotoxicology·Marina Cetkovic-CvrljeHwee Kiat Gong
Jun 17, 2008·Expert Opinion on Therapeutic Targets·Laura L RokoszMaria L Webb
May 23, 2012·Expert Opinion on Investigational Drugs·Tadeusz Robak, Ewa Robak
Feb 24, 2016·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Takanori TeshimaRobert Zeiser
Feb 24, 2016·Human Immunology·Petya Apostolova, Robert Zeiser
Oct 11, 2015·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Takanori TeshimaRobert Zeiser
Feb 13, 2016·Expert Review of Clinical Immunology·Leslie J CroffordPeggy L Kendall
Jul 17, 2007·American Journal of Reproductive Immunology : AJRI·Osmond J D'Cruz, Fatih M Uckun
May 16, 2013·Scandinavian Journal of Immunology·L VargasC I E Smith
Jan 11, 2013·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Kelli P MacDonaldPavan Reddy
Jul 15, 2017·Journal of Immunotoxicology·Marina Cetkovic-CvrljeKylie A Bruner

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