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

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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.

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Abbreviations

STING:

Stimulator of interferon gene

IFN:

Interferon

cGAS:

Cyclic GMP-AMP synthase

cGAMP:

Cyclic GMP-AMP

CDN:

Cyclic dinucleotide

ER:

Endoplasmic reticulum

TBK1:

TANK-binding kinase 1

IRF3:

Interferon regulatory factor 3

IL:

Interleukin

ISG:

Interferon-stimulated gene

CXCL10:

C-X-C motif chemokine ligand 10

SAVI:

STING-associated vasculopathy with onset in infancy

PTM:

Post-translational modifications

AGS:

Aicardi-Goutières syndrome

SLE:

Systemic lupus erythematosus

AKI:

Acute kidney injury

PROTAC:

Proteolysis-targeting chimera

IC50 :

Half-maximum inhibitory concentration

THP1:

Tohoku hospital pediatrics 1

CTD:

C-terminal domain

BMDM:

Mouse bone marrow-derived macrophage

MEF:

Mouse embryonic fibroblast

PCR:

Polymerase chain reaction

TNF:

Tumor necrosis factor

CCK-8:

Cell counting kit-8

ELISA:

Enzyme-linked immunosorbent assay

CC50 :

Concentration of 50% cytotoxicity

AUC:

Area under the curve

Cmax :

Maximum concentration

MRT:

Mean residence time

equiv:

Equivalent

DMF:

N,N-Dimethylformamide

DCM:

Dichloromethane

HATU:

2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

DIPEA:

N,N-Diisopropylethylamine

TBSCl:

tert-Butyldimethylsilyl chloride

MsCl:

methanesulfonyl chloride

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

SDS-PAGE:

sodium dodecyl sulfate – polyacrylamide gel electrophoresis

NC:

nitrocellulose

BSA:

bovine serum albumin

TBST:

tris-buffered saline + tween 20

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Acknowledgements

This work was supported by China Postdoctoral Science Foundation (Certificate Number: 2023T160663), Institutes for Drug Discovery and Development, Chinese Academy of Sciences (No. SIMM0320231002), the Natural Science Foundation of China for Innovation Research Group (81821005), the Shanghai Municipal Science and Technology Major Project, the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (2020CXJQ02), and the Shandong Laboratory Program (SYS202205).

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  1. Zechen Jin and Yan Zhang have contributed equally to this work.

Authors and 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

    Zechen Jin, Wenhu Duan & Hefeng Zhang

  2. School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China

    Zechen Jin & Wenhu Duan

  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

    Yan Zhang, Xin Luo, Meiyu Geng & Zuoquan Xie

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, 210023, China

    Xin Luo

  5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China

    Meiyu Geng & Wenhu Duan

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  1. Zechen Jin
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Contributions

ZJ and YZ contributed equally to this article. ZJ and YZ: Investigation, Methodology, Writing – original draft. XL: Investigation, Methodology. MG and WD: Conceptualization, Supervision, Writing – review & editing. ZX and HZ: Conceptualization, Investigation, Supervision, Writing – review & editing.

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Correspondence to Zuoquan Xie or Hefeng Zhang.

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Jin, Z., Zhang, Y., Luo, X. et al. Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10860-6

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