Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome
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 ALPK1 T237M 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.
Article Details
Authors (29)
Jieqing Fan
Danyang Liu
Zhu Ming
Chunyu Yan
Huaixin Dang
Yanfang Pan
Xiong Wei
Zhengle Zhao
Wenzhi Wang
Shuai Zhang
Linlin Chen
Shuo Cai
Centre of Biomedical Systems and Informatics, Zhejiang University—University of Edinburgh Institute, Zhejiang University School of Medicine
Jiangbin Ke
Yaru Luo
Linjie Rao
Jingjing Chen
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences
Zhenjie Chen
Junlin Zhou
Feixiang Chen
College of Smart Materials and Future Energy, State Key Laboratory of Molecular Engineering of Polymers
Xiaodi Duan
Boyue Ren
Tong-Ruei R. Li
Lawrence Melvin
Jeysen Yogaratnam
Vinit B. Mahajan
Hongmei Song
Henri Lichenstein
Tian Xu
Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States
Cong Xu
Department of Statistics and Data Science, College of Science