Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Colorectal cancer (CRC) is a major global health concern with high mortality rates.
• Dysregulation of the PI3K/AKT/mTOR signaling pathway, particularly via PI3Kα mutations, is common in CRC.
• There is a critical need for novel and effective therapeutic agents targeting CRC.

Purpose of the Study:

• To identify and characterize novel inhibitors targeting the PI3Kα subunit of the PI3K/AKT/mTOR pathway.
• To evaluate the efficacy and selectivity of a newly discovered compound, F0608-0019, against colorectal cancer cells.
• To elucidate the molecular interactions underlying the inhibitory activity of F0608-0019.

Main Methods:

• Structure-based virtual screening of approximately 3000 compounds.
• In vitro assessment of compound efficacy on colorectal cancer cell proliferation (HCT116 cells).
• Molecular dynamics simulations to analyze binding interactions with PI3Kα.

Main Results:

• Discovery of F0608-0019, a potent and selective PI3Kα inhibitor.
• F0608-0019 significantly inhibited HCT116 colorectal cancer cell proliferation with an IC50 of 12.14 µM.
• Molecular dynamics confirmed stable binding of F0608-0019 to critical amino acids in PI3Kα, ensuring high selectivity.

Conclusions:

• F0608-0019 is a promising lead compound for developing targeted colorectal cancer therapies.
• Selective inhibition of PI3Kα by F0608-0019 offers a potential new strategy for CRC treatment.
• Further development of F0608-0019 could lead to innovative treatments for PI3Kα-driven colorectal cancers.