2. Academic Validation
  3. Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis

Identification of two repurposed drugs targeting GSDMD oligomerization interface I to block pyroptosis

  • Cell Chem Biol. 2024 Dec 19;31(12):2024-2038.e7. doi: 10.1016/j.chembiol.2024.10.002.
Yingchao Hu 1,  Honghui Li 2,  Xiangyu Zhang 1,  Yuxian Song 1,  Jun Liu 3,  Jie Pu 3,  Shuang Wen 1,  Hongyang Xu 4,  Hongliang Xin 5,  Bingwei Wang 6,  Shuo Yang 7
Affiliations

Affiliations

  • 1 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Department of Immunology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China.
  • 2 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Department of Immunology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China; Department of Clinical Laboratory, The Third Affiliated Hospital of Nanchang University (The First Hospital of Nanchang), Nanchang 330008, Jiangxi, P.R. China.
  • 3 Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China.
  • 4 Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, China. Electronic address: [email protected].
  • 5 Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, 101 Longmian Road, Jiangning, Nanjing 211166, China. Electronic address: [email protected].
  • 6 Department of Pharmacology, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing 210023, China. Electronic address: [email protected].
  • 7 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Department of Immunology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
PMID: 39486414 DOI: 10.1016/j.chembiol.2024.10.002
Abstract

As an executor of Pyroptosis, gasdermin D (GSDMD) plays a critical role in inflammatory diseases and Cancer. Thus, GSDMD is currently being widely explored as a drug target. Existing inhibitors targeting GSDMD, such as necrosulfonamide, disulfiram, and fumarate, primarily prevent Pyroptosis by modifying human/mouse C191/C192 in the N-terminal fragment of GSDMD. However, cysteine modification can prevent the function of important proteins or Enzymes, thereby leading to adverse reactions. Here, we chose an alternative key intervention site for GSDMD activation, which is located at the oligomerization interface I of its pore-forming structure. Through high-throughput virtual and experimental screening and in combination with efficacy and pharmacological validation, we have identified two safe, specific "repurposed drugs" that potently suppress GSDMD-mediated Pyroptosis. Moreover, the candidates exhibited synergistic therapeutic effects of "1 + 1>2" in murine sepsis and tumorigenesis models. These recently identified GSDMD inhibitors hold great promise for clinical translation in the development of anti-inflammatory and anti-cancer immunotherapies.

Keywords

GSDMD; anti-cancer inhibitors; anti-inflammatory; oligomerization interface I.

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