Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC₅₀ = 89 nM) and remarkable PD-L1-degrading activity (DC₅₀ = 5.7 μM, D_max = 80% at 10 μM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3⁺ CD4⁺ helper T and CD3⁺ CD8⁺ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD₅₀ > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.

中文翻译：

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发现具有 PD-L1 下调/降解和抗肿瘤免疫作用的新型 HDAC3 抑制剂


靶向程序性细胞死亡-1/配体 1 (PD-1/PD-L1) 通路是最有前途的癌症治疗策略之一。研究表明HDAC抑制剂可以通过调节PD-L1的表达来增强抗肿瘤免疫反应。在此，我们设计并合成了一系列新型的基于酰肼的小分子HDAC抑制剂；其中，化合物HQ-30表现出选择性HDAC3抑制作用（IC ₅₀ = 89 nM）和显着的PD-L1降解活性（DC ₅₀ = 5.7 μM，D _max CD4 ⁺ 辅助T细胞和CD3 ⁺ CD8 ⁺ 细胞毒性T细胞的浸润，从而激活肿瘤免疫微环境。此外，HQ-30 具有良性毒性特征 (LD ₅₀ > 1000 mg/kg) 和良好的药代动力学特性 (F = 57%)。综上所述，HQ-30 作为一种基于小分子的肿瘤免疫治疗表观遗传调节剂值得进一步研究。