{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T23:18:29Z","timestamp":1780096709184,"version":"3.54.0"},"reference-count":47,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T00:00:00Z","timestamp":1656201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Science Foundation of China","award":["21977017"],"award-info":[{"award-number":["21977017"]}]},{"name":"Natural Science Foundation of China","award":["21472027"],"award-info":[{"award-number":["21472027"]}]},{"name":"Natural Science Foundation of China","award":["31270869"],"award-info":[{"award-number":["31270869"]}]},{"name":"Shanghai and Beijing Synchrotron Radiation Facility","award":["21977017"],"award-info":[{"award-number":["21977017"]}]},{"name":"Shanghai and Beijing Synchrotron Radiation Facility","award":["21472027"],"award-info":[{"award-number":["21472027"]}]},{"name":"Shanghai and Beijing Synchrotron Radiation Facility","award":["31270869"],"award-info":[{"award-number":["31270869"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cyclic guanosine monophosphate\u2013adenosine monophosphate synthase\u2013stimulator of interferon genes\u2013TANK-binding kinase 1\u2013interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2\u2032,3\u2032-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase\/phosphodiesterase 1 (ENPP1), which reduces the effect of tumor immunotherapy and promotes metastatic progression. In this investigation, the structure-based virtual screening strategy was adopted to discover eight candidate compounds containing zinc-binding quinazolin-4(3H)-one scaffold as ENPP1 inhibitors. Subsequently, these novel inhibitors targeting ENPP1 were synthesized and characterized by NMR and high-resolution mass spectra (HRMS). In bioassays, 7-fluoro-2-(((5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)thio)methyl)quina-zolin-4(3H)-one(compound 4e) showed excellent activity against the ENPP1 at the molecular and cellular levels, with IC50 values of 0.188 \u03bcM and 0.732 \u03bcM, respectively. Additionally, compound 4e had superior selectivity towards metastatic breast cancer cells (4T1) than towards normal cells (LO2 and 293T) in comparison with cisplatin, indicating that compound 4e can potentially be used in metastatic breast cancer therapy. On the other hand, compound 4e upgraded the expression levels of IFN-\u03b2 in vivo by preventing the ENPP1 from hydrolyzing the cGAMP to stimulate a more potent innate immune response. Therefore, this compound might be applied to boost antitumor immunity for cancer immunotherapy. Overall, our work provides a strategy for the development of a promising drug candidate targeting ENPP1 for tumor immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms23137104","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T21:01:41Z","timestamp":1656277301000},"page":"7104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Development of Novel Ecto-Nucleotide Pyrophosphatase\/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy"],"prefix":"10.3390","volume":"23","author":[{"given":"Xiang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daojing","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangshi","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1111\/jcpt.12304","article-title":"Pembrolizumab: A novel antiprogrammed death 1 (PD-1) monoclonal antibody for treatment of metastatic melanoma","volume":"40","author":"Tan","year":"2015","journal-title":"J. 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