A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy

作者：Yin, Lei; Li, Heng; Liu, Wenjian; Yao, Zhenglin; Cheng, Zhenzhen; Zhang, Huabei^*; Zou, Hui^*

来源：European Journal of Medicinal Chemistry, 2018, 144: 1-28.

DOI：10.1016/j.ejmech.2017.12.003

• Glioblastoma
• CNS
• CDK4/6 inhibitor
• U87MG
• Pharmacokinetics
• Structure-activity relationship

Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the K-p value of 4.10 and the K-p,K-uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p < 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.

• 出版日期2018-1-20
• 单位北京师范大学