Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors

Zechen Jin; Yan Zhang; Xin Luo; Meiyu Geng; Wenhu Duan; Zuoquan Xie; Hefeng Zhang

doi:10.1007/s11030-024-10860-6

Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors

Mol Divers. 2024 Apr 29. doi: 10.1007/s11030-024-10860-6. Online ahead of print.

Authors

Zechen Jin^#^{1

2}, Yan Zhang^#³, Xin Luo^{3

4}, Meiyu Geng^{3

5}, Wenhu Duan^{1

2

5}, Zuoquan Xie⁶, Hefeng Zhang⁷

Affiliations

¹ Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
² School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
³ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
⁴ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, 210023, China.
⁵ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. zqxie@simm.ac.cn.
⁷ Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. zhanghefeng1@simm.ac.cn.

^# Contributed equally.

PMID: 38683489
DOI: 10.1007/s11030-024-10860-6

Abstract

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Keywords: Inflammation; Inhibitor; Interferon-stimulated gene 15; Stimulator of interferon gene; Thiazolecarboxamide.