Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors. (31st December 2022)

• Record Type: Journal Article
• Authors: Jeong, Hee Jin; Lee, Hye Lim; Kim, Sung Joon; Jeong, Jeong Hyun; Ji, Su Hyun; Kim, Han Byeol; Kang, Miso; Chung, Hwan Won; Park, Chan Sun; Choo, Hyunah; Yoon, Hyo Jae; Kim, Nam-Jung; Lee, Duck-Hyung; Lee, Sanghee; Han, Seo-Jung
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 2434
• Page End: 2451
• Publication Date: 2022-12-31
• Subjects: ENPP1 -- STING -- innate immunity -- cancer immunotherapy; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2119566
• Languages: English
• ISSNs: 1475-6366

Abstract

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.