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Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.

ABSTRACT: FOXM1 is a potent oncogenic transcription factor essential for cancer initiation, progression, and drug resistance. FOXM1 regulatory network is a major predictor of adverse outcomes in various human cancers. Inhibition of FOXM1 transcription factor function is a potential strategy in cancer treatment. In this study, we performed structure-based in silico screening to discover small molecules targeting the FOXM1 DNA-binding domain (DBD). Compound XST-20 was identified to effectively suppress FOXM1 transcriptional activities and inhibit ovarian cancer cell proliferation. XST-20 directly interacts with the FOXM1 DNA-binding domain determined by SPR assay. Furthermore, XST-20 was found to significantly reduce the colony-forming efficiency and induce cell cycle arrest and apoptosis. Our study provides a lead compound of FOXM1 inhibitor which may serve as a potential targeted therapy agent for ovarian cancer.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC9184618 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.

Zhang Zaixin Z Xue Si-Tu ST Gao Yan Y Li Yingwei Y Zhou Ziying Z Wang Jing J Li Zhuorong Z Liu Zhaojian Z

Cell death discovery 20220609 1

FOXM1 is a potent oncogenic transcription factor essential for cancer initiation, progression, and drug resistance. FOXM1 regulatory network is a major predictor of adverse outcomes in various human cancers. Inhibition of FOXM1 transcription factor function is a potential strategy in cancer treatment. In this study, we performed structure-based in silico screening to discover small molecules targeting the FOXM1 DNA-binding domain (DBD). Compound XST-20 was identified to effectively suppress FOXM ...[more]

PMID: 35680842

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Project description:BACKGROUND: Accurate small molecule binding site information for a protein can facilitate studies in drug docking, drug discovery and function prediction, but small molecule binding site protein sequence annotation is sparse. The Small Molecule Interaction Database (SMID), a database of protein domain-small molecule interactions, was created using structural data from the Protein Data Bank (PDB). More importantly it provides a means to predict small molecule binding sites on proteins with a known or unknown structure and unlike prior approaches, removes large numbers of false positive hits arising from transitive alignment errors, non-biologically significant small molecules and crystallographic conditions that overpredict ion binding sites. DESCRIPTION: Using a set of co-crystallized protein-small molecule structures as a starting point, SMID interactions were generated by identifying protein domains that bind to small molecules, using NCBI's Reverse Position Specific BLAST (RPS-BLAST) algorithm. SMID records are available for viewing at http://smid.blueprint.org. The SMID-BLAST tool provides accurate transitive annotation of small-molecule binding sites for proteins not found in the PDB. Given a protein sequence, SMID-BLAST identifies domains using RPS-BLAST and then lists potential small molecule ligands based on SMID records, as well as their aligned binding sites. A heuristic ligand score is calculated based on E-value, ligand residue identity and domain entropy to assign a level of confidence to hits found. SMID-BLAST predictions were validated against a set of 793 experimental small molecule interactions from the PDB, of which 472 (60%) of predicted interactions identically matched the experimental small molecule and of these, 344 had greater than 80% of the binding site residues correctly identified. Further, we estimate that 45% of predictions which were not observed in the PDB validation set may be true positives. CONCLUSION: By focusing on protein domain-small molecule interactions, SMID is able to cluster similar interactions and detect subtle binding patterns that would not otherwise be obvious. Using SMID-BLAST, small molecule targets can be predicted for any protein sequence, with the only limitation being that the small molecule must exist in the PDB. Validation results and specific examples within illustrate that SMID-BLAST has a high degree of accuracy in terms of predicting both the small molecule ligand and binding site residue positions for a query protein.

Dataset Information

Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.

Publications

Small molecule targeting FOXM1 DNA binding domain exhibits anti-tumor activity in ovarian cancer.

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