期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 75, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128947
关键词
ENPP1; Innate immunity; STING; Cancer immunotherapy
资金
- KIST Institutional Program [2E31624, 2E31690, 2V09235, 2E31629, 2E3162D]
- 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)
- National Research Council of Science & Technology (NST) - Korea government (MSIT) [CPS21061-100]
- Korea Drug Development Fund - Ministry of Science and ICT, Ministry of Trade, Industry
- Ministry of Health and Welfare, Republic of Korea [HN22C0063000022]
- Starting growth Technological R & D Program - Ministry of SMEs and Startups (MSS, Korea) [S3017522]
- Ministry of SMEs and Startups (MSS, Korea)
- Korea Evaluation Institute of Industrial Technology (KEIT) [HN22C0063000022] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Korea Technology & Information Promotion Agency for SMEs (TIPA) [S3017522] 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)
This study discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives are potent ENPP1 inhibitors with high microsomal stabilities.
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).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据