Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors

Abstract

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.

Keywords:

• ENPP1
• STING
• innate immunity
• cancer immunotherapy

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

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].