Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

Hee Jin Jeong, Hye Lim Lee, Sung Joon Kim, Jeong Hyun Jeong, Su Hyun Ji, Han Byeol Kim, Miso Kang, Hwan Won Chung, Chan Sun Park, Hyunah Choo, Hyo Jae Yoon, Nam Jung Kim, Duck Hyung Lee, Sang Hee Lee, Seo Jung Han

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-β and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

Original languageEnglish
Pages (from-to)2434-2451
Number of pages18
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Issue number1
Publication statusPublished - 2022

Bibliographical note

Funding Information:
This study was supported by KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E3162D, 2E31512 and 2E31524], the National Research Foundation of Korea (NRF) [2021R1C1C1005134], the Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT [NRF-2020M1A2A2079798]. This research was also supported by the National Research Council of Science & Technology (NST) granted by the Korea government(MSIT) [No. CPS21061-100]. Additionally, this research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare [HN22C0063000022, Republic of Korea].

Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


  • ENPP1
  • cancer immunotherapy
  • innate immunity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery


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