TY - JOUR
T1 - Multiomics Study of a Novel Naturally Derived Small Molecule, NSC772864, as a Potential Inhibitor of Proto-Oncogenes Regulating Cell Cycle Progression in Colorectal Cancer
AU - Mokgautsi, Ntlotlang
AU - Kuo, Yu Cheng
AU - Chen, Chien Hsin
AU - Huang, Yan Jiun
AU - Wu, Alexander T.H.
AU - Huang, Hsu Shan
N1 - Funding Information:
The National Science and Technology Council, Taiwan, grant number NSTC111-2314-B-038-017 and the Ministry of Science and Technology, Taiwan, grant number MOST111-2314-B-038-122 awarded to H.-S. Huang. ATH Wu is also funded by, The National Science and Technology Council, Taiwan, Grant # (111-2314-B-038-098) and (111-2314-B-038-142).
Publisher Copyright:
© 2023 by the authors.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - colorectal cancer
KW - drug resistance
KW - molecular docking simulation
KW - protein–ligand interaction
KW - small molecule
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U2 - 10.3390/cells12020340
DO - 10.3390/cells12020340
M3 - Article
C2 - 36672275
AN - SCOPUS:85146807153
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 2
M1 - 340
ER -