NDLI: Integrated discovery of FOXO1–DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer

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Integrated discovery of FOXO1–DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer

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Molecular BioSystems Vol - 13 Issue - 1

Molecular BioSystems Vol -12

Molecular BioSystems Vol -9

Molecular BioSystems Vol -8

Molecular BioSystems Vol -7

Molecular BioSystems Vol -6

Molecular BioSystems Vol -5

Molecular BioSystems Vol -4

Molecular BioSystems Vol -3

Molecular BioSystems Vol -2

Integrated discovery of FOXO1–DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer

Content Provider	Royal Society of Chemistry (RSC)
Author	Sun, Yingjia Hou, Jingwen Ai, Xinghao Lu, Shun Liu, Ruijun Shen, Shengping Li, Ziming Ye, Xiangyun
Copyright Year	2017
Abstract	The transcription factor forkhead box O1 (FOXO1) negatively regulates activated EGFR signaling by turning on the gene expression of tumor suppressor Kruppel-like factor 6. Here, we propose that the chemosensitivity to anti-EGFR-based lung cancer therapy can be restored by stabilization of the FOXO1–DNA complex architecture using small-molecule marine natural medicines. A synthetic protocol that integrates computational ligand–protein–DNA binding analysis and an experimental fluorescence binding assay was applied against a large library of structurally diverse, drug-like marine natural products to discover novel stabilizers of DNA-bound FOXO1 conformation. The screening utilized chemical similarity analysis to exclude structurally redundant compounds, and then carried out high-throughput molecular docking and computational binding analysis to identify potential marine natural product candidates. Consequently, eight commercially available hits were selected and tested in vitro, from which four marine natural product compounds (tanzawaic acid D, hymenidin, cribrostatin 6 and barbamide) were found to have high or moderate potency to selectively bind to the FOXO1 DNA-binding domain (DBD) in the presence of its cognate DNA partner. Atomistic molecular dynamics (MD) simulations revealed that the identified stabilizers do not directly interact with DNA; instead, they can effectively stabilize the free FOXO1 DBD domain in the DNA-bound conformation and thus promote the binding of FOXO1 to DNA.
Starting Page	330
Ending Page	337
Page Count	8
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	13
Issue Number	2
Journal	Molecular BioSystems
DOI	10.1039/c6mb00678g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Docking (molecular) Fluorescence Natural product Molecular dynamics EGFR Epidermal growth factor receptor Kruppel-like factors DNA-binding domain Gene Carboxylic acid DNA Gene regulatory network Library Transcription factor Protein structure Non-small-cell lung carcinoma Chemical substance
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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Integrated discovery of FOXO1–DNA stabilizers from marine natural products to restore chemosensitivity to anti-EGFR-based therapy for metastatic lung cancer