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

Guan, Dezhong; Fang, Lincheng; Feng, Mingshun; Guo, Shi; Xie, Lingfeng; Chen, Chao; Sun, Xue; Wu, Qingyun; Yuan, Xinrui; Xie, Zuoquan; Zhou, Jinpei; Zhang, Huibin

doi:10.1016/j.ejmech.2024.116211

European Journal of Medicinal Chemistry

2024

DOI: 10.1016/j.ejmech.2024.116211

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

Dezhong Guan,

Lincheng Fang,

Mingshun Feng

et al.

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2024

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Cited by 2 publications

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Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

Gao,

Hou,

et al. 2024

European Journal of Medicinal Chemistry

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Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

Gao,

Hou,

et al. 2024

European Journal of Medicinal Chemistry

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

Zhan,

Zhang,

Cao

et al. 2024

J. Med. Chem.

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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 IC 50 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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Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects

Cited by 2 publications

References 76 publications

Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

Discovery of orally bioavailable phosphonate prodrugs of potent ENPP1 inhibitors for cancer treatment

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

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