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
  • 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.

Products