Constructing triazole-modified quinazoline derivatives as selective c-MYC G-quadruplex ligands and potent anticancer...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• The c-MYC oncogene is crucial in tumorigenesis and frequently overexpressed in cancers.
• G-quadruplex (G4) structures in the c-MYC promoter can suppress its expression.
• Targeting c-MYC G4 with small molecules is a potential cancer therapy strategy.

Purpose of the Study:

• To develop novel triazole-modified quinazoline (TMQ) derivatives as selective ligands for the c-MYC G-quadruplex.
• To evaluate the ability of these derivatives to inhibit c-MYC transcription and suppress cancer cell proliferation.
• To identify lead compounds with improved c-MYC G4 stabilizing and anticancer properties.

Main Methods:

• Synthesis of TMQ derivatives from a 4-anilinoquinazoline lead using click chemistry.
• Assessment of c-MYC G4 stabilizing potential and antiproliferation activity in cancer cell lines.
• Evaluation of compound selectivity for c-MYC G4 and its effect on c-MYC transcription.

Main Results:

• A series of TMQ derivatives were synthesized and evaluated.
• A strong correlation was observed between c-MYC G4 stabilizing ability and antiproliferation activity, especially in HCT116 colorectal cancer cells.
• Compound A6 demonstrated superior selectivity for c-MYC G4 stabilization and c-MYC transcription inhibition compared to the lead compound.
• A6 induced G4 formation, selectively inhibited G4-related c-MYC transcription, and suppressed HCT116 cell progression.

Conclusions:

• TMQ derivatives, particularly compound A6, are effective c-MYC G4 stabilizers and transcription inhibitors.
• Compound A6 shows promise as a selective c-MYC-targeting therapeutic agent for cancers driven by c-MYC.
• These findings provide valuable insights for the design of optimized c-MYC G4-targeting ligands for cancer therapy.