TOPIC

Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy

Journal

Journal of Medicinal Chemistry

Author(s)

He, J., Ma, X., Sun, J., Chen, M., Xu, L., Song, Z., Ding, C., Meng, L., & Zhang, A.

Year

2025

ENPP1, a transmembrane glycoprotein overexpressed in various cancers, has become a promising target for tumor immunotherapy. Several ENPP1 inhibitors have been reported, but only a few have been validated in vivo. Herein, based on the reported inhibitors 3 and 6, we carried out a structural optimization by designing a variety of 8-methoxyquinazoline and its equivalent 8-methoxy-3-cyano-quinoline derivatives featuring bridged- or spirobicycles as the linker. Compound 30 was identified as a promising ENPP1 inhibitor. This compound exhibited IC50 values of 8.05 nM against ENPP1 and 1.53 nM in MDA-MB-231 cells with no significant inhibitory effects against both hERG and a panel of 97 kinases. It effectively activated the intracellular STING pathway by inhibiting cGAMP degradation. In the murine CT-26 tumor model, 30 inhibited tumor growth with increased immune cell infiltration in the tumor microenvironment and enhanced type I interferon responses. Meanwhile, compound 30 synergically enhanced the antitumor efficacy of anti-PD-L1 antibody.

Keywords: Q1 2025

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