biostudies-literatureUnknown16(1)Fan JROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare genetic disease caused by variants in alpha-kinase 1 (ALPK1) resulting in downstream pro-inflammatory signaling mediated by the TIFA/TRAF6/NF-κB pathway. Here, we report the design of an ALPK1 inhibitor, DF-003, with pharmacokinetic properties suitable for daily oral dosing. In biochemical assays, DF-003 potently inhibits human ALPK1 (IC₅₀ = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC₅₀ = 16 nM). When tested against a panel of 394 human kinases, DF-003 exhibits ≥860-fold selectivity over the closest kinase. In cell-based assays, DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1[T237M] mNature communications8251https://www.ebi.ac.uk/biostudies/studies/S-EPMC12420824biostudies-literatureDiscovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome.PMC12420824Cai SKe JWei XZhang SLichenstein HZhao ZMing ZFan JChen ZMelvin LYogaratnam JWang WRao LZhou JPan YMahajan VBChen JChen LChen FXu CSong HDang HRen BXu TYan CLuo YLiu DDuan XLi TRfalseDiscovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome.ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome is a rare genetic disease caused by variants in alpha-kinase 1 (ALPK1) resulting in downstream pro-inflammatory signaling mediated by the TIFA/TRAF6/NF-κB pathway. Here, we report the design of an ALPK1 inhibitor, DF-003, with pharmacokinetic properties suitable for daily oral dosing. In biochemical assays, DF-003 potently inhibits human ALPK1 (IC₅₀ = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC₅₀ = 16 nM). When tested against a panel of 394 human kinases, DF-003 exhibits ≥860-fold selectivity over the closest kinase. In cell-based assays, DF-003 suppresses inflammatory cytokine signaling mediated both by wild-type ALPK1 and the disease-causing ALPK1[T237M] m2025-01-01T00:00:00Z2025 Sep2026-06-02T20:19:02.613Z2026-04-20T03:10:12.899ZS-EPMC124208244092590010.1038/s41467-025-63731-5