Cheong Jaeeun Yunseong Jang Jeong Hee Jin Kim, Sung Joon Park, Kichul OH DO HEE Yu, Ahran Park, Chan Sun Han, Seojung 2024-01-12T02:36:08Z 2024-01-12T02:36:08Z 2022-08-24 2022-11 0960-894X https://pubs.kist.re.kr/handle/201004/75971 Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structur-e-activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors. Also, compounds 46 and 23 possessed high microsomal stabilities in human, rat, and mouse liver microsome. Addi-tionally, CYPs (1A2, 2C9, 2C19, 2D6, and 3A4) were not inhibited by 46 and 23. Molecular dynamics simulations provided an insight of binding modes between ENPP1 and compounds (46 and 23). English Pergamon Press Ltd. Discovery of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives as novel ENPP1 inhibitors Article 10.1016/j.bmcl.2022.128947 1 Bioorganic & Medicinal Chemistry Letters, v.75 Bioorganic & Medicinal Chemistry Letters 75 N scie scopus 000862283900006 Chemistry, Medicinal Chemistry, Organic Pharmacology & Pharmacy Chemistry Article ENPP1 Innate immunity STING Cancer immunotherapy