Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual...

Area of Science:

• * Pharmacology and Medicinal Chemistry
• * Cancer Biology
• * Molecular Biology

Background:

• * Targeting cell cycle regulators like cyclin-dependent kinase 4 (Cdk4) and tubulin polymerization are established strategies to inhibit cancer cell proliferation.
• * Previous research identified fascaplysin derivatives as dual inhibitors of Cdk4 and tubulin, showing efficacy in preclinical models.
• * Developing novel, potent inhibitors with dual-targeting capabilities remains a key objective in cancer drug discovery.

Purpose of the Study:

• * To identify novel compounds that inhibit both Cdk4 and tubulin polymerization.
• * To evaluate the efficacy of identified compounds in blocking cancer cell cycle progression at critical phases (G0/G1 and M).
• * To demonstrate the utility of ligand-based virtual screening in designing multi-target inhibitors for cancer treatment.

Main Methods:

• * Screening of a 59-compound quinazolinone library using ligand-based virtual screening.
• * Biochemical assays to determine IC50 values for Cdk4 and tubulin polymerization inhibition.
• * Cancer cell cycle analysis and molecular modeling studies with Cdk4 and tubulin crystal structures.

Main Results:

• * Identification of Cink4T, a quinazolinone derivative, as a potent inhibitor of Cdk4 (IC50 = 0.47 μM) and tubulin polymerization (IC50 = 0.6 μM).
• * Cink4T demonstrated high selectivity for Cdk4 over other cyclin-dependent kinases (Cdk1, Cdk2, Cdk6, Cdk9).
• * Cell cycle analysis confirmed Cink4T's ability to arrest cancer cells in both G0/G1 and M phases, consistent with dual inhibition.

Conclusions:

• * Virtual screening is an effective strategy for designing novel small molecules with dual inhibitory activity against key cancer targets.
• * Cink4T represents a promising lead compound for cancer therapy due to its potent dual inhibition of Cdk4 and tubulin.
• * Targeting multiple cell cycle phases simultaneously offers a robust approach to overcome resistance and enhance therapeutic outcomes in cancer treatment.