State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan Engineering Research Center for Anticancer Targeted Protein Pharmaceuticals, Hunan University, Changsha, Hunan, 410082, China.
Cell Death Dis. 2023 Aug 19;14(8):533. doi: 10.1038/s41419-023-06056-9.
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.
阻断蛋白质-蛋白质相互作用（PPIs）已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结构，可以合理设计干扰 PPI 的干扰肽。转录因子 FOXM1 在多种癌症中过度表达，被认为是癌症治疗药物开发的有效靶点。我们使用合理的设计方法，从 FOXM1 C 端序列生成了一个肽文库，并筛选了与 FOXM1 结合的肽。结合 FOXM1 结合和细胞抑制结果，我们获得了一种 FOXM1 靶向干扰肽 M1-20，它是从天然母肽优化而来的 D-反向肽。M1-20 具有改善的稳定性特征，可抑制癌细胞的增殖和迁移，并诱导其凋亡。在机制上，M1-20 通过破坏 MuvB 复合物与转录共激活因子 CBP 之间的相互作用来抑制 FOXM1 的转录活性。这些结果与 M1-20 在野生型小鼠中没有明显的毒性和副作用的情况下抑制癌症进展和转移的结果一致。这些发现表明，M1-20 有可能被开发为针对 FOXM1 的抗癌药物候选物。
