Design and Synthesis of Triazole-Containing HDAC Inhibitors That Induce Antitumor Effects and Immune Response

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.