{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["16(1)"],"submitter":["Fan J"],"pubmed_abstract":["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 (IC<sub>50</sub> = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC<sub>50</sub> = 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] m"],"journal":["Nature communications"],"pagination":["8251"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12420824"],"repository":["biostudies-literature"],"pubmed_title":["Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome."],"pmcid":["PMC12420824"],"pubmed_authors":["Cai S","Ke J","Wei X","Zhang S","Lichenstein H","Zhao Z","Ming Z","Fan J","Chen Z","Melvin L","Yogaratnam J","Wang W","Rao L","Zhou J","Pan Y","Mahajan VB","Chen J","Chen L","Chen F","Xu C","Song H","Dang H","Ren B","Xu T","Yan C","Luo Y","Liu D","Duan X","Li TR"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome.","description":"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 (IC<sub>50</sub> = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC<sub>50</sub> = 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] m","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Sep","modification":"2026-06-02T20:19:02.613Z","creation":"2026-04-20T03:10:12.899Z"},"accession":"S-EPMC12420824","cross_references":{"pubmed":["40925900"],"doi":["10.1038/s41467-025-63731-5"]}}