A series of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors based on the resorcinol diphenyl ether scaffold were discovered by incorporating hydrophilic moieties into the side chain and converting into the corresponding hydrochloride salt. Among these compounds, P18 showed the highest inhibitory activity against PD-1/PD-L1 with an IC₅₀ value of 9.1 nM in a homogeneous time-resolved fluorescence binding assay. Besides, P18 promoted HepG2 cell death dose dependently in a HepG2/PD-L1 and Jurkat/PD-1 coculture cell model. Further, P18 demonstrated significantly higher water solubility (17.61 mg/mL) and improved pharmacokinetics (e.g., t_1/2 of ∼20 h and oral bioavailability of 12%) than the previous analogues. Moreover, P18 was highly effective in suppressing tumor growth in an immune checkpoint humanized mouse model without apparent toxicity. Collectively, these results suggest that compound P18 represents a promising PD-1/PD-L1 inhibitor worthy of further investigation as a potential anticancer agent.

中文翻译：

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发现新型和高效间苯二酚二苄基醚为基础的PD-1 / PD-L1抑制剂，具有改善的药物样和药代动力学特性，可用于癌症治疗

通过将亲水性基团掺入侧链并转化为相应的盐酸盐，发现了一系列基于间苯二酚二苯醚支架的程序性细胞死亡-1（PD-1）/程序性细胞死亡配体1（PD-L1）抑制剂。在这些化合物中，P18在均相时间分辨荧光结合试验中显示出对PD-1 / PD-L1的最高抑制活性，IC ₅₀值为9.1 nM。此外，在HepG2 / PD-L1和Jurkat / PD-1共培养细胞模型中，P18促进HepG2细胞死亡剂量依赖性。此外，P18证明显著更高的水溶解度（17.61毫克/毫升）和改善的药物动力学（例如，吨_1/2约20小时内，口服生物利用度为12％）。此外，P18在免疫检查点人源化小鼠模型中抑制肿瘤生长非常有效，而没有明显的毒性。总的来说，这些结果表明化合物P18代表有希望的PD-1 / PD-L1抑制剂，作为潜在的抗癌剂值得进一步研究。