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Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes

Ntlotlang Mokgautsi^1,2, Yu-Cheng Kuo^3,4, Chien-Hsin Chen⁵

¹Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.

|January 21, 2023

Abstract:

Colorectal cancer (CRC) is one of the most prevalent malignant tumors, and it contributes to high numbers of deaths globally. Although advances in understanding CRC molecular mechanisms have shed significant light on its pathogenicity, current treatment options, including combined chemotherapy and molecular-targeted agents, are still limited due to resistance, with almost 25% of patients developing distant metastasis. Therefore, identifying novel biomarkers for early diagnosis is crucial, as they will also influence strategies for new targeted therapies. The proto-oncogene, c-Met, a tyrosine kinase that promotes cell proliferation, motility, and invasion; c-MYC, a transcription factor associated with the modulation of the cell cycle, proliferation, apoptosis; and cyclin D1 (CCND1), an essential regulatory protein in the cell cycle, all play crucial roles in cancer progression. In the present study, we explored computational simulations through bioinformatics analysis and identified the overexpression of c-Met/GSK3β/MYC/CCND1 oncogenic signatures that were associated with cancer progression, drug resistance, metastasis, and poor clinical outcomes in CRC. We further demonstrated the anticancer activities of our newly synthesized quinoline-derived compound, NSC772864, against panels of the National Cancer Institute's human CRC cell lines. The compound exhibited cytotoxic activities against various CRC cell lines. Using target prediction tools, we found that c-Met/GSK3β/MYC/CCND1 were target genes for the NSC772864 compound. Subsequently, we performed in silico molecular docking to investigate protein-ligand interactions and discovered that NSC772864 exhibited higher binding affinities with these oncogenes compared to FDA-approved drugs. These findings strongly suggest that NSC772864 is a novel and potential antiCRC agent.

Insights

Novel compound NSC772864 shows promise against colorectal cancer (CRC). Bioinformatics identified key oncogenes (c-Met/GSK3β/MYC/CCND1) linked to CRC progression, and NSC772864 effectively targeted these, suggesting a new therapeutic strategy.

Area of Science:

Oncology
Molecular Biology
Bioinformatics

Background:

Colorectal cancer (CRC) presents a significant global health burden with limited treatment efficacy due to resistance and metastasis.
Existing therapies for CRC, including chemotherapy and targeted agents, face challenges, necessitating novel therapeutic strategies and biomarkers for early detection.
Key oncogenes like c-Met, c-MYC, and cyclin D1 (CCND1) are implicated in CRC progression, influencing cell proliferation, motility, invasion, and clinical outcomes.

Purpose of the Study:

To identify novel oncogenic signatures associated with colorectal cancer progression and poor clinical outcomes.
To evaluate the anticancer potential of a newly synthesized quinoline-derived compound, NSC772864, against human CRC cell lines.
To investigate the molecular mechanisms underlying NSC772864's activity, including its interaction with identified oncogenic targets.

Main Methods:

Bioinformatics analysis and computational simulations were employed to identify key oncogenic signatures in CRC.
In vitro cytotoxicity assays were performed using a panel of National Cancer Institute human CRC cell lines to assess NSC772864's efficacy.
Target prediction tools and in silico molecular docking were utilized to determine NSC772864's binding affinities with identified oncogenes.

Main Results:

Overexpression of c-Met/GSK3β/MYC/CCND1 oncogenic signatures was identified and correlated with CRC progression, drug resistance, metastasis, and adverse clinical outcomes.
The synthesized compound NSC772864 demonstrated significant cytotoxic activities across various CRC cell lines.
NSC772864 exhibited higher binding affinities to the targeted oncogenes (c-Met/GSK3β/MYC/CCND1) compared to FDA-approved drugs, as revealed by molecular docking studies.

Conclusions:

The identified c-Met/GSK3β/MYC/CCND1 oncogenic signature serves as a potential biomarker for CRC progression and poor prognosis.
NSC772864 displays potent anticancer activities against CRC cells by targeting key oncogenic pathways.
NSC772864 represents a promising novel therapeutic agent for colorectal cancer, warranting further investigation and development.

Read full analysis

Keywords:

colorectal cancer drug resistance molecular docking simulation protein–ligand interaction small molecule

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