TLR8 agonist Motolimod-induced inflammatory death for treatment of acute myeloid leukemia
Wei Yang, Xiongfei Sun, Shuai Liu, Ying Xu, Yunlei Li, Xiao‐Ru Huang, Kaiqing Liu, Longyi Mao, Shasha Min, Linjiang Liu, Shi Li, Yuqi Zhu, Yu Zhang, Xina Xie, Kui Xu, Changqing Sun, Jie Yan, Zesong Li
Abstract
The clinical treatment of AML is dominated by "7 + 3" therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation.