Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects

  • Eur J Med Chem. 2024 Mar 5:267:116211. doi: 10.1016/j.ejmech.2024.116211.
Dezhong Guan  1 ,  Lincheng Fang  2 ,  Mingshun Feng  3 ,  Shi Guo  4 ,  Lingfeng Xie  4 ,  Chao Chen  4 ,  Xue Sun  1 ,  Qingyun Wu  4 ,  Xinrui Yuan  4 ,  Zuoquan Xie  5 ,  Jinpei Zhou  6 ,  Huibin Zhang  7
Affiliations
  • 1. Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009, Nanjing, China.
  • 2. Peking University Shenzhen Graduate School, Shenzhen, China.
  • 3. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
  • 5. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: [email protected].
  • 6. Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009, Nanjing, China. Electronic address: [email protected].
  • 7. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: [email protected].
PMID: 38359537 DOI: 10.1016/j.ejmech.2024.116211
Abstract

The Cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration. ENPP1 has been validated to play important roles in diabetes, cancers, and Cardiovascular Disease and now become a promising target for tumor immunotherapy. Several ENPP1 inhibitors under development have shown good anti-tumor effects alone or in combination with Other agents in clinical and preclinical researches. In this review, the biological profiles of ENPP1 were described, and the structures and the structure-activity relationships (SAR) of the known ENPP1 inhibitors were summarized. This review also provided the prospects and challenges in the development of ENPP1 inhibitors.

Keywords
2′,3′-cGAMP; ENPP1 inhibitors; Tumor immunotherapy; cGAS-STING pathway.