Discovery 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 (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] mutant. Using mice heterozygous for wild-type human ALPK1 and ALPK1<sup>T237M</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2025-09-09
DOI
https://doi.org/10.1038/s41467-025-63731-5
Citations
3
Primary Topic
Protein Kinase Regulation and GTPase Signaling
Type
article
Field-Weighted Citation Impact
2.42

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article

Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome

Vinit B. Mahajan, Xu Tian, Huaixin Dang, Yaru Luo et al.
3 citations
Nature Communications
Protein Kinase Regulation and GTPase Signaling
2.42
article

Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome

Vinit B. Mahajan, Xu Tian, Huaixin Dang, Yaru Luo, Cong Xu, Jia Ke, Xiaodi Duan, Henri S. Lichenstein, T. LI, Jeysen Yogaratnam, Baihui Ren, Hongmei Song, L Depamphilis Melvin, Shengguan Cai, Zhengyang Zhao, Wei Xiong, Ming Zhu, Zhenjie Chen, Linlin Chen, Shuai Zhang, Jingjing Chen, Wenzhi Wang, Junlin Zhou, Danyang Liu, Yanfang Pan, Feixiang Chen, Yan Chen, L. V. Subba Rao, Jieqing Fan
article en
3 citations

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] mutant. Using mice heterozygous for wild-type human ALPK1 and ALPK1<sup>T237M</sup> 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.

Nature CommunicationsVol. 16(1)
Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Peking Union Medical College Hospital (CN), Zhejiang Lab (CN), Shanghai Drug Administration (CN), ZheJiang Institute For Food and Drug Control (CN), Smith-Kettlewell Eye Research Institute (US), Guilford College (US), Stanford University (US)
Chinese Academy of Sciences, Fudan University, Tsinghua University, University of Chinese Academy of Sciences
Openalex Percentile: Top 10%
Protein Kinase Regulation and GTPase Signaling
2.42
DOIOpen Access PDFOpenAlex
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