Design and Synthesis of Novel 5,6,7,8-Tetrahydropyrido[2,3-

Background: VCP/p97 plays an important role in endoplasmic reticulum related degradation pathways, and inhibition of p97 was shown to induce ER stress and subsequently cell death in a variety of solid tumors and hematoma. For acute myeloid leukemia (AML) cells, inhibition of p97 activity leads to the accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Methods: We have designed and synthesized a series of novel 5,6,7,8-tetrahydropyridine[2,3-d]pyrimidine derivatives. After synthesizing all the target compounds, the optimal lead compound was identified through screening for enzyme inhibitory activity and anti-tumor cell proliferation activity. Subsequently, the liver microsomal stability and pharmacokinetics of the lead compound was investigated. Finally, the in vivo antitumor efficacy of the lead compound was evaluated to assess its potential for the treatment of acute myeloid leukemia (AML). Results: Compound Conclusion: These results indicate that compound V12 is a potent p97 inhibitor with excellent in vitro and in vivo antitumor efficacy, which might provide a new therapeutic strategy for the treatment of AML.