Identification of Novel PKC Alpha Inhibitors: Structural and Functional Characterization Using In Silico and In Vitro...

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Cancer Research

Background:

• Protein Kinase C alpha (PKCα) is a critical regulator of cellular signaling pathways.
• Dysregulation of PKCα is frequently observed in various types of breast cancer.
• There is an unmet need for selective and safe PKCα inhibitors for therapeutic applications.

Purpose of the Study:

• To identify and characterize novel inhibitors of Protein Kinase C alpha (PKCα).
• To utilize computational and experimental approaches for drug discovery.
• To evaluate the potential of identified compounds as therapeutic agents for breast cancer.

Main Methods:

• Structure-based virtual screening of a chemical library against the PKCα receptor.
• Molecular docking, binding free energy calculations, and ADMET profiling.
• Molecular dynamics simulations for complex stability, kinase assays, and MTT assays for cytotoxicity.

Main Results:

• Two novel compounds, P1 and P2, with distinct scaffolds demonstrated strong binding and stability with PKCα.
• P1 and P2 exhibited potent inhibition of PKCα's ATP-binding activity with low nanomolar IC50 values (0.92 nM and 15.27 nM, respectively).
• Both compounds induced dose-dependent cytotoxicity in ER+ and triple-negative breast cancer cell lines.

Conclusions:

• This study successfully identified two novel, structurally diverse, and potent PKCα inhibitors.
• The identified compounds possess significant therapeutic potential for breast cancer treatment.
• These inhibitors provide a foundation for developing selective agents targeting PKCα-driven malignancies.