{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T05:06:49Z","timestamp":1779772009113,"version":"3.53.1"},"reference-count":32,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,5,14]]},"abstract":"<jats:p>\n                    Monoclonal antibodies targeting the programmed cell death protein 1\/programmed cell death ligand 1 (PD\u20101\/PD\u2010L1) immune checkpoint have demonstrated clinical efficacy in cancer immunotherapy. However, antibody\u2010based immunotherapies still suffer from unavoidable limitations, such as suboptimal pharmacokinetic properties and potential immunogenicity. In contrast, small\u2010molecule PD\u20101\/PD\u2010L1 inhibitors may complement antibody therapeutics and provide an alternative modality. In this study, we designed and synthesized a series of biphenyl\u2010based inhibitors featuring an oxadiazole motif and a conformationally constrained benzo[d]oxazole framework. SAR analysis revealed that introducing a 1,2,4\u2010oxadiazole ring directly linked to the distal phenyl ring of the biphenyl scaffold, together with cyclization at the ether linkage to construct a rigid benzo[d]oxazole framework connected to the proximal phenyl ring, afforded overall high potency. Notably, compound\n                    <jats:bold>I\u20105<\/jats:bold>\n                    emerged as the lead compound, exhibiting an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 8.04\u2009nM for inhibition of the PD\u20101\/PD\u2010L1 interaction. At the cellular level,\n                    <jats:bold>I\u20105<\/jats:bold>\n                    displayed low nonspecific cytotoxicity toward tumor cells, restored T\u2010cell immune function by promoting interferon\u2010\u03b3 (IFN\u2010\u03b3) secretion, and markedly enhanced peripheral blood mononuclear cell (PBMC)\u2013mediated cytotoxicity against MDA\u2010MB\u2010231 tumor cells. Collectively, these results suggest that compound\n                    <jats:bold>I\u20105<\/jats:bold>\n                    is a promising small\u2010molecule PD\u20101\/PD\u2010L1 inhibitor and warrants further in\u2010depth investigation.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70287","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T03:01:47Z","timestamp":1779159707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Biological Evaluation of Small\u2010Molecule PD\u20101\/PD\u2010L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7840-2469","authenticated-orcid":false,"given":"Bo","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"Ding","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingfeng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezhong","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2115-6317","authenticated-orcid":false,"given":"Huibin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Drug Discovery State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5904-6164","authenticated-orcid":false,"given":"Jinpei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry China Pharmaceutical University  Nanjing P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8172"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2016.144"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105123"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27172"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102017\u201007\u2010740993"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1994.1562"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22079"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2326"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21349"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.124"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611533104"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13954"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090331"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u20106143.2012.04224.x"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010021\u201000431\u20104"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111876"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100643"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2016.29"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8730"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00010"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01682"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.1c00646"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2020.113001"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113998"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2019.111856"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113637"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01684"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115468"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.09.010"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00293"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20050"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2016.1206527"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70287","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70287","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70287","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T04:57:51Z","timestamp":1779771471000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":32,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,5,14]]}},"alternative-id":["10.1002\/cmdc.70287"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70287","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,14]]},"assertion":[{"value":"2026-01-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70287"}}