Fan Jieqing, Liu Danyang, Ming Zhu, Yan Chunyu, Dang Huaixin, Pan Yanfang, Wei Xiong, Zhao Zhengle, Wang Wenzhi, Zhang Shuai, Chen Linlin, Cai Shuo, Ke Jiangbin, Luo Yaru, Rao Linjie, Chen Jingjing, Chen Zhenjie, Zhou Junlin, Chen Feixiang, Duan Xiaodi, Ren Boyue, Li Tong-Ruei R, Melvin Lawrence, Yogaratnam Jeysen, Mahajan Vinit B, Song Hongmei, Lichenstein Henri, Xu Tian, Xu Cong
Shanghai Yao Yuan Biotechnology Ltd (Drug Farm), Shanghai, China.
Zhejiang Yao Yuan Biotechnology Ltd, Jiashan, Zhejiang, China.
Nat Commun. 2025 Sep 9;16(1):8251. doi: 10.1038/s41467-025-63731-5.
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 = 1.5 nM) and the ROSAH disease-causing mutant ALPK1[T237M] (IC = 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 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.
ROSAH（视网膜营养不良、视神经水肿、脾肿大、无汗和头痛）综合征是一种罕见的遗传性疾病，由α-激酶1（ALPK1）的变异引起，导致由TIFA/TRAF6/NF-κB途径介导的下游促炎信号传导。在此，我们报告了一种ALPK1抑制剂DF-003的设计，其药代动力学特性适合每日口服给药。在生化分析中，DF-003能有效抑制人ALPK1（IC = 1.5 nM）和导致ROSAH疾病的突变型ALPK1[T237M]（IC = 16 nM）。在针对394种人类激酶进行测试时，DF-003对最接近的激酶表现出≥860倍的选择性。在基于细胞的分析中，DF-003可抑制由野生型ALPK1和致病型ALPK1[T237M]突变体介导的炎性细胞因子信号传导。利用野生型人ALPK1和已建立的ALPK1杂合小鼠来模拟ROSAH综合征，这些小鼠在视网膜、视神经和皮质中表现出视网膜小胶质细胞浸润、星形胶质细胞活化和炎性细胞因子上调，我们发现口服DF-003足以抑制这些炎性表型。
