Design, Synthesis, and Biological Evaluation of Small‐Molecule PD‐1/PD‐L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton
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| Format: | Artículo Open Access |
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2026
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| _version_ | 1867016055846600704 |
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| author | Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou |
| author_facet | Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou |
| collection | Wiley Open Access |
| contents | Design, Synthesis, and Biological Evaluation of Small‐Molecule PD‐1/PD‐L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou ChemMedChem Monoclonal antibodies targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1) immune checkpoint have demonstrated clinical efficacy in cancer immunotherapy. However, antibody‐based immunotherapies still suffer from unavoidable limitations, such as suboptimal pharmacokinetic properties and potential immunogenicity. In contrast, small‐molecule PD‐1/PD‐L1 inhibitors may complement antibody therapeutics and provide an alternative modality. In this study, we designed and synthesized a series of biphenyl‐based inhibitors featuring an oxadiazole motif and a conformationally constrained benzo[d]oxazole framework. SAR analysis revealed that introducing a 1,2,4‐oxadiazole 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 I‐5 emerged as the lead compound, exhibiting an IC 50 of 8.04 nM for inhibition of the PD‐1/PD‐L1 interaction. At the cellular level, I‐5 displayed low nonspecific cytotoxicity toward tumor cells, restored T‐cell immune function by promoting interferon‐γ (IFN‐γ) secretion, and markedly enhanced peripheral blood mononuclear cell (PBMC)–mediated cytotoxicity against MDA‐MB‐231 tumor cells. Collectively, these results suggest that compound I‐5 is a promising small‐molecule PD‐1/PD‐L1 inhibitor and warrants further in‐depth investigation. 10.1002/cmdc.70287 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/cmdc.70287 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_cmdc_70287 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2026 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Design, Synthesis, and Biological Evaluation of Small‐Molecule PD‐1/PD‐L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou ChemMedChem Design, Synthesis, and Biological Evaluation of Small‐Molecule PD‐1/PD‐L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton Bo Wei Xueling Ding Peiyu Zhu Lingfeng Xie Dezhong Guan Xiaoyi Zhang Huibin Zhang Jinpei Zhou ChemMedChem Monoclonal antibodies targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1) immune checkpoint have demonstrated clinical efficacy in cancer immunotherapy. However, antibody‐based immunotherapies still suffer from unavoidable limitations, such as suboptimal pharmacokinetic properties and potential immunogenicity. In contrast, small‐molecule PD‐1/PD‐L1 inhibitors may complement antibody therapeutics and provide an alternative modality. In this study, we designed and synthesized a series of biphenyl‐based inhibitors featuring an oxadiazole motif and a conformationally constrained benzo[d]oxazole framework. SAR analysis revealed that introducing a 1,2,4‐oxadiazole 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 I‐5 emerged as the lead compound, exhibiting an IC 50 of 8.04 nM for inhibition of the PD‐1/PD‐L1 interaction. At the cellular level, I‐5 displayed low nonspecific cytotoxicity toward tumor cells, restored T‐cell immune function by promoting interferon‐γ (IFN‐γ) secretion, and markedly enhanced peripheral blood mononuclear cell (PBMC)–mediated cytotoxicity against MDA‐MB‐231 tumor cells. Collectively, these results suggest that compound I‐5 is a promising small‐molecule PD‐1/PD‐L1 inhibitor and warrants further in‐depth investigation. 10.1002/cmdc.70287 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Design, Synthesis, and Biological Evaluation of Small‐Molecule PD‐1/PD‐L1 Inhibitors Bearing a Rigid Benz[d]oxazole Skeleton |
| topic | ChemMedChem |
| url | https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.70287 |