JH-X-119-01

JH-X-119-01 is a potent and selective interleukin-1 receptor-associated kinases 1 (IRAK1) inhibitor. JH-X-119-01 ameliorates LPS-induced sepsis in mice^[1]. JH-X-119-01 inhibits IRAK1 biochemically with an apparent IC₅₀ of 9 nM while exhibiting no inhibition of IRAK4 at concentrations up to 10 μM^[2]. In Vitro: JH-X-119-01 (10 μM) decreases phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. JH-X-119-01 selectively inhibits IRAK1 phosphorylation^[1]. JH-X-119-01 exhibits off-target inhibition of only two additional kinases, YSK4 and MEK3. Dose response analysis reveals an IC₅₀ of 57 nM for YSK4^[2]. JH-X-119-01 shows moderate cell killing effects in a panel of Waldenström’s macroglobulinemia (WM) cells, Diffused Large B-cell Lymphoma (DLBCL) cells, and lymphoma cells expressing mutant MYD88, with EC₅₀s ranging from 0.59 to 9.72 μM^[2]. In Vivo: JH-X-119-01 improves survival and decreases immunopathies of LPS-challenged mice. JH-X-119-01 increases survival of mice at the dose of 5 mg/kg body weight. Survival is further improved when the dose is increased to 10 mg/kg^[1].