破坏蛋白质间相互作用 (PPIs) 已经成为癌症药物开发的一种有前途的策略。基于介导这些相互作用的天然序列的结构，可以有目的地设计干扰蛋白质间相互作用的肽。转录因子FOXM1在多种癌症中过度表达，并被认为是癌症治疗药物开发的有效靶点。利用有理设计方法，我们从FOXM1 C端序列中生成了一个肽库，并筛选了与FOXM1结合的肽。结合FOXM1结合和细胞抑制结果，我们获得了一个名为M1-20的FOXM1靶向干扰肽，它是从天然母体肽优化到D-反向干扰肽。具有改进的稳定性特性，M1-20抑制了癌细胞的增殖和迁移，并诱导了细胞凋亡。在机制上，M1-20通过破坏其与MuvB复合物和转录共激活因子CBP之间的相互作用来抑制FOXM1的转录活性。这些结果与M1-20在野生型小鼠中抑制癌症进展和转移而没有明显的毒性和副作用的结果一致。这些发现揭示了M1-20有潜力成为针对FOXM1的抗癌药物候选物。© 2023. 作者.

Disrupting protein-protein interactions (PPIs) has emerged as a promising strategy for cancer drug development. Interfering peptides disrupting PPIs can be rationally designed based on the structures of natural sequences mediating these interactions. Transcription factor FOXM1 overexpresses in multiple cancers and is considered an effective target for cancer therapeutic drug development. Using a rational design approach, we have generated a peptide library from the FOXM1 C-terminal sequence and screened FOXM1-binding peptides. Combining FOXM1 binding and cell inhibitory results, we have obtained a FOXM1-targeting interfering peptide M1-20 that is optimized from the natural parent peptide to the D-retro-inverso peptide. With improved stability characteristics, M1-20 inhibits proliferation and migration, and induces apoptosis of cancer cells. Mechanistically, M1-20 inhibits FOXM1 transcriptional activities by disrupting its interaction between the MuvB complex and the transcriptional co-activator CBP. These are consistent with the results that M1-20 suppresses cancer progression and metastasis without noticeable toxic and side effects in wild-type mice. These findings reveal that M1-20 has the potential to be developed as an anti-cancer drug candidate targeting FOXM1.© 2023. The Author(s).