Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 37, Issue 1, Pages 2434-2451Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2022.2119566
Keywords
ENPP1; STING; innate immunity; cancer immunotherapy
Funding
- KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E31512, 2E31524]
- National Research Foundation of Korea (NRF) [2021R1C1C1005134]
- Technology Development Program to Solve Climate Change of the National Research Foundation (NRF) of Korea - Ministry of Science and ICT [NRF-2020M1A2A2079798]
- National Research Council of Science & Technology (NST) - Korea government(MSIT) [CPS21061-100]
- Korea Drug Development Fund - Ministry of Science and ICT
- Ministry of Health and Welfare [Republic of Korea] [HN22C0063000022]
- Ministry of Trade, Industry, and Energy
- Korea Evaluation Institute of Industrial Technology (KEIT) [HN22C0063000022] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Council of Science & Technology (NST), Republic of Korea [CPS21061-100] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2021R1C1C1005134] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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In this study, novel ENPP1 inhibitors were designed and synthesized to stimulate the STING pathway and inhibit tumor growth. The compound 18p showed high potency against ENPP1 and activated the STING pathway, leading to the induction of cytokines and inhibition of tumor growth in a mouse model.
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-beta 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.
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