 Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndromeJieqing Fan,
Danyang Liu,
Zhu Ming,
Chunyu Yan,
Huaixin Dang,
Yanfang Pan,
Xiong Wei,
Zhengle Zhao,
Wenzhi Wang,
Shuai Zhang,
Linlin Chen,
Shuo Cai,
Jiangbin Ke,
Yaru Luo,
Linjie Rao,
Jingjing Chen,
Zhenjie Chen,
Junlin Zhou,
Feixiang Chen,
Xiaodi Duan,
Boyue Ren,
Tong-Ruei R. Li,
Lawrence Melvin,
Jeysen Yogaratnam,
Vinit B. Mahajan,
Hongmei Song,
Henri Lichenstein,
Tian Xu () and
Cong Xu ()
Nature Communications, 2025, vol. 16, issue 1, 1-15 Abstract: 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 (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] mutant. Using mice heterozygous for wild-type human ALPK1 and ALPK1T237M established to model ROSAH syndrome that exhibit retinal microglial infiltration, astrocyte activation, and inflammatory cytokine upregulation in the retina, optic nerve, and cortex, we show that orally administered DF-003 is sufficient to inhibit these inflammatory phenotypes. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63731-5 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-025-63731-5 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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