Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Txinno Bioscience INC, 338 Gwanggyojungang-ro, Suji-gu, Yongin-si, Gyeonggi-do 16942, Republic of Korea.
Bioorg Med Chem Lett. 2022 Nov 1;75:128947. doi: 10.1016/j.bmcl.2022.128947. Epub 2022 Aug 19.
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 structure-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. Additionally, 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).
核苷酸焦磷酸酶/磷酸二酯酶-1（ENPP1）负调控干扰素基因刺激物（STING）通路。我们发现 3,4-二氢嘧啶并[4,5-d]嘧啶-2(1H)-酮和 3,4-二氢吡啶并[2,3-d]嘧啶-2(1H)-酮衍生物对 ENPP1 具有抑制活性。构效关系（SAR）研究确定了 46 和 23 为有效的 ENPP1 抑制剂。此外，化合物 46 和 23 在人、大鼠和小鼠肝微粒体中具有较高的微粒体稳定性。此外，化合物 46 和 23 不抑制 CYP（1A2、2C9、2C19、2D6 和 3A4）。分子动力学模拟提供了 ENPP1 与化合物（46 和 23）之间结合模式的深入了解。
