2. Academic Validation
  3. Identification of 5,7-Dihydro-6 H-pyrrolo[2,3- d]pyrimidin-6-one Derivatives as ENPP1 Inhibitors for STING Pathway-Mediated Immunotherapy

Identification of 5,7-Dihydro-6 H-pyrrolo[2,3- d]pyrimidin-6-one Derivatives as ENPP1 Inhibitors for STING Pathway-Mediated Immunotherapy

  • J Med Chem. 2025 Aug 14;68(15):16059-16075. doi: 10.1021/acs.jmedchem.5c01021.
Su Hyun Ji 1 2,  Miso Kang 3,  Hyomin Ahn 4,  Soo Yeon Baek 3,  In-Gyun Lee 5 6,  Hanul Jeon 5,  Hwan Won Chung 7,  Dong Kyun Han 1,  Seoyeong Yang 4 8,  Hyebin Lee 4 9,  Yeseul Kim 3 10,  Ji Hun Wi 3 11,  Jeehee Lee 3 12,  Younghun Yoo 3 13,  Sungbae Kang 3 14,  Mihue Jang 3 14 13,  Byungsun Jeon 3 13,  Nam-Jung Kim 14 15,  Chiman Song 4 13,  Sanghee Lee 3 14,  Seo-Jung Han 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Sogang University, 35, Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
  • 2 Center for Nano Materials, Sogang University, 35, Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
  • 3 Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4 Chemical and Biological Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 5 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
  • 6 Natural Products Research Institute, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
  • 7 Computational Science Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 8 College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Republic of Korea.
  • 9 Department of Pharmacology, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 10 Department of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 11 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 12 Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea.
  • 13 Division of Bio-Medical Science and Technology, KIST School, Korea University of Science and Technology (UST), 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 14 KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.
  • 15 Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Dongdae-mun-gu, Seoul 02447, Republic of Korea.
PMID: 40711563 DOI: 10.1021/acs.jmedchem.5c01021
Abstract

A novel small-molecule ENPP1 inhibitor, compound 31 featuring a pyrrolopyrimidinone core, was identified. Compound 31 exhibited potent ENPP1 inhibition with an IC50 of 14.68 nM and effectively activated the STING pathway in cell lines. In addition, 31 promoted cytokine release, thereby enhancing innate immune response. Moreover, 31 demonstrated favorable ADMET properties. Compound 31 displayed significant antitumor efficacy in 4T1 and CT26 syngeneic mouse models without notable toxicity. These findings highlight the potential of 31 as a promising compound for Cancer Immunotherapy by enhancing STING-mediated immune activation and improving responses to immune checkpoint inhibitors.

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