Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response
Nan Sun, Kexin Yang, Wenzhong Yan, Mingyue Yao, Chengcheng Yu, Wenwen Duan, Xiaoke Gu, Dong Guo, Hualiang Jiang, Chengying Xie, Jianjun Cheng
Abstract
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.