Related Experiment Video
Updated: Sep 18, 2025
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Identification and characterization of a potent peptide inhibitor targeting FOXM1 in cancer therapy
Anping Liang1, Miao Chang2, Zhixian Shang3
1Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drug, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031 Sichuan Province, China; School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031 Sichuan Province, China.
Abstract:
FOXM1 is a critical oncogenic transcription factor involved in almost all cancer hallmark pathways across all cancer types. The clinical translation and therapeutic application have been hampered mainly by the lack of highly efficient, specific and mechanism-of-action defined FOXM1 inhibitors. In our previous work, we had obtained a FOXM1-targeting peptide P201 from a commercial phage random peptide libraries. However, the efficacy of P201 needed to be further improved and its underlying mechanisms in cancers were not fully understood. Here, through alanine scanning mutagenesis of P201 and the construction and selection of a biased phage peptide library, a novel and optimized peptide, P49, was identified. Compared to P201, 9R-P49 demonstrated enhanced binding affinity, improved hydrophilicity, and increased cytotoxicity against cancer cells. Mechanistically, 9R-P49 binds specifically to the DNA-binding domain of FOXM1, resulting in reduced FOXM1 expression and competitive disruption of FOXM1-DNA interactions, which results in transcriptional downregulation. Additionally, 9R-P49 synergistically enhanced the effect of Sorafenib in vitro and significantly inhibited tumor growth when co-administered with Sorafenib in HCCLM3 xenograft models. Furthermore, 9R-P49 potentiated the efficacy of anti-PD1 immunotherapy by downregulating PD-L1 expression and activating antitumor immune responses in mice. Taken together, our study highlights the potential of 9R-P49 as a novel and optimized FOXM1-targeted peptide inhibitor in clinical translation beyond combination therapies.
Insights
A new peptide, 9R-P49, effectively targets the FOXM1 (Forkhead box protein M1) oncogene. This optimized peptide enhances cancer cell killing and shows promise in combination therapies for improved cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- FOXM1 (Forkhead box protein M1) is a key oncogenic transcription factor driving cancer progression.
- Existing FOXM1 inhibitors lack efficiency and specificity, hindering clinical applications.
- Previous research identified peptide P201, but its efficacy and mechanisms required further improvement.
Purpose of the Study:
- To develop an optimized FOXM1-targeting peptide with enhanced efficacy and defined mechanisms.
- To evaluate the therapeutic potential of the novel peptide 9R-P49 in preclinical cancer models.
- To explore combination strategies involving 9R-P49 with existing therapies.
Main Methods:
- Alanine scanning mutagenesis and biased phage display library construction for peptide optimization.
- In vitro assays to assess binding affinity, cytotoxicity, and molecular mechanisms.
- In vivo studies using HCCLM3 xenograft models and combination therapy with Sorafenib.
- Evaluation of synergistic effects with anti-PD1 immunotherapy in mouse models.
Main Results:
- The novel peptide 9R-P49 exhibits superior binding affinity, hydrophilicity, and cytotoxicity compared to P201.
- 9R-P49 specifically targets the FOXM1 DNA-binding domain, reducing FOXM1 expression and DNA interactions.
- 9R-P49 demonstrates synergistic effects with Sorafenib in vitro and in vivo tumor inhibition.
- 9R-P49 potentiates anti-PD1 immunotherapy by downregulating PD-L1 and enhancing anti-tumor immunity.
Conclusions:
- 9R-P49 is a highly effective and optimized FOXM1-targeted peptide inhibitor.
- 9R-P49 shows significant potential for clinical translation, particularly in combination therapies.
- This study provides a novel therapeutic strategy targeting FOXM1 for various cancers.
More Related Videos
14:28Peptide-based Identification of Functional Motifs and their Binding Partners
Published on: June 30, 2013
10:18Author Spotlight: Magnetic Fluorescent Bead-Based Dual-Reporter Flow Analysis of PDL1-Vaxx Peptide Vaccine-Induced Antibody Blockade of the PD-1/PD-L1 Interaction
Published on: July 7, 2023
