Discovery of Imidazo[1,2-<i>a</i>]pyrazine Derivatives as Potent ENPP1 Inhibitors
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-<i>a</i>]pyrazine derivative <b>7</b> as a highly potent and selective ENPP1 inhibitor. Compound <b>7</b> demonstrated substantial inhibitory activity against ENPP1 with an IC<sub>50</sub> value of 5.70 or 9.68 nM while showing weak inhibition against ENPP2 and ENPP3. Furthermore, compound <b>7</b> was shown to enhance the mRNA expression of cGAMP-induced STING pathway downstream target genes, such as <i>IFNB1</i>, <i>CXCL10</i>, and <i>IL</i>6. <i>In vivo</i> pharmacokinetic and antitumor studies showed promising results, with <b>7</b> not only exhibiting efficient pharmacokinetic properties but also enhancing the antitumor efficacy of the anti-PD-1 antibody. Treatment with <b>7</b> (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.
Authors
- Xiaowei Wu (ORCID: https://orcid.org/0000-0001-7248-9149)
- Haifang Meng
- Rongrong Cui (ORCID: https://orcid.org/0000-0002-6799-894X)
- Mingyue Zheng (ORCID: https://orcid.org/0000-0002-3323-3092)
- Qiang Wang (ORCID: https://orcid.org/0000-0002-5480-7980)
- Yingying Zhang (ORCID: https://orcid.org/0000-0002-3951-0345)
- Yitian Wang (ORCID: https://orcid.org/0000-0003-3064-1020)
- Shiping Zhan (ORCID: https://orcid.org/0000-0003-1192-4236)
- Sulin Zhang (ORCID: https://orcid.org/0000-0002-9167-4689)
- Lin Huang (ORCID: https://orcid.org/0009-0005-2632-9511)
- Jie Yu (ORCID: https://orcid.org/0009-0006-5415-4891)
- Ruirui Yang (ORCID: https://orcid.org/0000-0001-6510-4327)
- Tian Cao
Institutions
- University of Science and Technology of China (CN)
- Guiyang Medical University (CN)
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
- Anhui Provincial Hospital (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01634
- Citations
- 7
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- National Natural Science Foundation of China
- Youth Innovation Promotion Association of the Chinese Academy of Sciences