Jh-X-119-01 is a highly potent and selective covalent inhibitor of IRAK1. JH-X-119-01 inhibited IRAK1 biochemically with an IC50 of 9.3 nM while exhibiting no inhibition of IRAK4 at concentrations up to 10 µM, and showed exceptional Kinome selectivity with off-target inhibition of only two kinases, YSK4 and MEK3. Intact protein MS labeling studies confirmed that JH-X-119-01 irreversibly labels IRAK1 at C302. Jh-X-119-01 exhibited cytotoxic activity at single digit micromolar concentrations in a panel of WM (Waldenström's macroglobulinemia), DLBCL (Diffused Large B-cell Lymphoma), and lymphoma cell lines expressing MYD88. Cotreatment of JH-X-119-01 with the BTK inhibitor ibrutinib resulted in synergistic killing effects in these systems. Importantly, the combination of JH-X-119-01 with Ibrutinib led to synergistic tumor cell killing in MYD88 mutated WM and ABC-DLBCL cells, and suppression of NF-ĸB activation. JH-X-119-01 shows synergistic tumor cell killing with ibrutinib in MYD88 mutated WM and ABC-DLBCL cells. In vivo PK studies revealed a favorable profile for JH-X-119-01 with a moderate half-life of 1.61 hours, a Cmax of 9.95 µM, and a low clearance of 18.84 mL/min/kg when dosed IV[1].
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