组蛋白去乙酰化酶（HDAC）是表观遗传学的抗肿瘤药物靶点，但大多数现有的HDAC抑制剂显示出有限的抗肿瘤活性，并且它们的使用常常伴随着严重的不良反应。为了克服这些问题，我们设计并合成了一系列含有三唑基的化合物作为新型HDAC抑制剂。其中，19h化合物表现出强有力和选择性的HDAC1抑制作用，在体外具有良好的抗增殖活性和卓越的药代动力学特性。19h化合物明显抑制了人类肿瘤异种移植物在裸鼠中的生长以及在免疫能力强的小鼠中MC38结肠癌的生长。在MC38模型中，19h化合物增加了脾脏CD4+T效应细胞的比例，并在与mPD-1抗体结合时促进了6只动物中5只完全肿瘤消退。这些结果表明，选择性I类HDAC抑制剂对肿瘤的生长具有直接的抑制作用和间接的免疫细胞介导的抗肿瘤效应，并且与免疫检查点抑制剂具有协同作用。

Histone deacetylase (HDAC) is an epigenetic antitumor drug target, but most existing HDAC inhibitors show limited antitumor activity and their use is often accompanied by serious adverse effects. To overcome these problems, we designed and synthesized a series of triazole-containing compounds as novel HDAC inhibitors. Among them, compound 19h exhibited potent and selective inhibition of HDAC1, with good antiproliferative activity in vitro and an excellent pharmacokinetic profile. Compound 19h significantly inhibited the growth of human tumor xenografts in nude mice and murine tumor growth in immune-competent mice bearing MC38 colon cancer. In the MC38 model, 19h increased the ratio of splenic CD4+ T effector cells and promoted complete tumor regression in 5/6 animals when combined with the mPD-1 antibody. These results suggested that selective class I HDAC inhibitors exert direct tumor growth inhibition and indirect immune cell-mediated antitumor effects and are synergistic with immune checkpoint inhibitors.