Design, synthesis, and biological evaluation of aryl urea derivatives as novel STING inhibitors based on SN-011

Chaoxin Wang; Runan Zheng; Qing Zhang; Juanhong Li; Shangran Zhang; Suyang Sun; Xiaoan Wen; Qinglong Xu; Haoliang Yuan; Liu Liu; Zhiqi Feng; Hongbin Sun; Liang Dai

doi:10.1016/j.bmc.2026.118749

Design, synthesis, and biological evaluation of aryl urea derivatives as novel STING inhibitors based on SN-011

Bioorg Med Chem. 2026 Oct:141:118749. doi: 10.1016/j.bmc.2026.118749. Epub 2026 Jul 7.

Authors

Chaoxin Wang¹, Runan Zheng², Qing Zhang¹, Juanhong Li¹, Shangran Zhang¹, Suyang Sun¹, Xiaoan Wen³, Qinglong Xu¹, Haoliang Yuan¹, Liu Liu¹, Zhiqi Feng¹, Hongbin Sun⁴, Liang Dai⁵

Affiliations

¹ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
² Animal Experiment Center of China Pharmaceutical University, China Pharmaceutical University, Nanjing 211198, China.
³ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China.
⁴ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China. Electronic address: hongbinsun@cpu.edu.cn.
⁵ Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401135, China. Electronic address: dailiang@cpu.edu.cn.

PMID: 42430810
DOI: 10.1016/j.bmc.2026.118749

Abstract

Abnormal activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway drives excessive inflammatory responses and plays a key role in the pathological process of various inflammatory diseases, and thus STING inhibitors hold great promise as anti-inflammatory agents. In this work, we report a series of novel aryl urea derivatives as STING inhibitors. Among the 40 synthesized derivatives, compound W23 exhibited potent inhibitory activity against STING and effectively blocked STING downstream signaling transduction. Furthermore, topical administration of W23 ameliorated psoriatic skin lesions and attenuated cutaneous inflammation in imiquimod-induced psoriasis mouse model, with efficacy comparable to the commercial benvitimod cream. Collectively, compound W23 represents a potent STING inhibitor with the potential to reverse STING-mediated inflammatory responses and alleviate immune disorders. Our work provides some novel SN-011 derivatives as STING inhibitors for future research.

Keywords: Aryl urea; Inhibitor; Psoriasis; Stimulator of interferon gene.

MeSH terms

Animals
Dose-Response Relationship, Drug
Drug Design*
Humans
Membrane Proteins* / antagonists & inhibitors
Membrane Proteins* / metabolism
Mice
Molecular Structure
Psoriasis* / chemically induced
Psoriasis* / drug therapy
STING Protein
Structure-Activity Relationship
Urea* / analogs & derivatives
Urea* / chemical synthesis
Urea* / chemistry
Urea* / pharmacology
cGAS-STING Signaling Pathway

Substances

Urea
Membrane Proteins
STING Protein
STING1 protein, human
Sting1 protein, mouse