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More recently, the advent of small molecule inhibitors that target the PD-1\/PD-L1 axis have shown promising cellular inhibitory activity and the potential to counteract the disadvantages of mAbs. In this study, structure-based virtual screening identified small molecule inhibitors that effectively inhibited the PD-1\/PD-L1 interaction. Six of those small molecule inhibitors were applied to cell-based experiments targeting PD-1: CH-1, CH-2, CH-3, CH-4, CH-5, and CH-6. Of all 6, CH-4 displayed the lowest cytotoxicity and strongest inhibitory activity towards the PD-1\/PD-L1 interaction. The experiments revealed that CH-4 inhibited the interaction of soluble form PD-L1 (sPD-L1) with PD-1 surface protein expressed by KG-1 cells. Investigations into CH-4 analogs revealed that CH-4.7 effectively blocked the PD-1\/sPD-L1 interaction, but sustained the secretion of interleukin-2 and interferon-\u03b3 by Jurkat cells. Our experiments revealed a novel small molecule inhibitor that blocks the interaction of PD-1\/sPD-L1 and potentially offers an alternative PD-1 target for immune checkpoint therapy.<\/jats:p>","DOI":"10.1038\/s41598-021-03590-4","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T11:03:21Z","timestamp":1641553401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["In vitro characterization of a small molecule PD-1 inhibitor that targets the PD-l\/PD-L1 interaction"],"prefix":"10.1038","volume":"12","author":[{"given":"Chih-Hao","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Min","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hao","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Chien","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Cheng","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-En","family":"Tzeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"3590_CR1","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","volume":"192","author":"GJ Freeman","year":"2000","unstructured":"Freeman, G. 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