Design and Synthesis of Novel 5,6,7,8-Tetrahydropyrido[2,3-D]pyrimidine Derivatives as VCP/p97 Inhibitors for the Treatment of Acute Myeloid Leukemia (AML).

Abstract

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 V12 and metabolite V13, which was screened by enzyme inhibition activity, showed strong inhibitory activities against a variety of cell lines with IC₅₀ values less than 1 μM. In pharmacokinetic studies, after intragastric administration of V12 (10 mg/kg) in SD rats, V12 was rapidly metabolized toV13. The oral half-life of V13 in plasma was 3.5 h, and the C_max and AUC_0-inf values of V13 reached 1070 ng/mL and 1412 ng•h/mL, respectively, showing good pharmacokinetic properties. In addition, compound V12 showed a strong anti-tumor therapeutic effect in vivo and lower toxic side effects in the human AML (Molm-13) mouse xenograft model.

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.