{Reference Type}: Journal Article
{Title}: CS12192: A novel selective and potent JAK3 inhibitor mitigates acute graft-versus-host disease in bone marrow transplantation.
{Author}: Huang S;Yang Q;Zhou Y;Li L;Shan S;
{Journal}: Transpl Immunol
{Volume}: 85
{Issue}: 0
{Year}: 2024 Jun 25
{Factor}: 2.032
{DOI}: 10.1016/j.trim.2024.102075
{Abstract}: <B>BACKGROUND: </B>Despite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases.<BR><B>METHODS: </B>We evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model.<BR><B>RESULTS: </B>CS12192, starting at a concentration of 0.5 μM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05).<BR><B>CONCLUSIONS: </B>CS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.