Discovery of Imidazo[1,2- a]pyrazine Derivatives as Potent ENPP1 Inhibitors

  • J Med Chem. 2024 Oct 24;67(20):18317-18333. doi: 10.1021/acs.jmedchem.4c01634.
Shiping Zhan  1  2 ,  Yingying Zhang  3  4 ,  Tian Cao  1  5 ,  Ruirui Yang  6 ,  Qiang Wang  1 ,  Lin Huang  1 ,  Rongrong Cui  6 ,  Jie Yu  6 ,  Haifang Meng  1 ,  Yitian Wang  6 ,  Sulin Zhang  6 ,  Mingyue Zheng  6  3  4 ,  Xiaowei Wu  6  1  2
Affiliations
  • 1. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 2. School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
  • 3. School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
  • 4. The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 5. School of Pharmacy, Guizhou Medical University, Guiyang 550014, China.
  • 6. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 39357030 DOI: 10.1021/acs.jmedchem.4c01634
Abstract

ENPP1 acts as a negative regulator of the cGAS-STING pathway through the hydrolysis of 2'3'-cGAMP. Inhibitors of ENPP1 are regarded as promising agents for stimulating the immune response in Cancer Immunotherapy. This study describes the identification and optimization of imidazo[1,2-a]pyrazine derivative 7 as a highly potent and selective ENPP1 inhibitor. Compound 7 demonstrated substantial inhibitory activity against ENPP1 with an IC50 value of 5.70 or 9.68 nM while showing weak inhibition against ENPP2 and ENPP3. Furthermore, compound 7 was shown to enhance the mRNA expression of cGAMP-induced STING pathway downstream target genes, such as IFNB1, CXCL10, and IL6. In vivo pharmacokinetic and antitumor studies showed promising results, with 7 not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with 7 (80 mg/kg) combined with anti-PD-1 antibody achieved a tumor growth inhibition rate of 77.7% and improved survival in a murine model.

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