2. Academic Validation
  3. Design, Synthesis, and Pharmacological Evaluation of Quinazoline and Quinoline Derivatives as Potent ENPP1 Inhibitors for Cancer Immunotherapy

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

  • J Med Chem. 2025 Feb 20. doi: 10.1021/acs.jmedchem.4c03207.
Jie He 1 2,  Xiaoyu Ma 3,  Jia Sun 1 2,  Manman Chen 3,  Lan Xu 3,  Zilan Song 1 2,  Chunyong Ding 1 2,  Linghua Meng 3,  Ao Zhang 1 2 4
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
  • 4 The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China.
PMID: 39973889 DOI: 10.1021/acs.jmedchem.4c03207
Abstract

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.

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