Phthalimide conjugations for the degradation of oncogenic PI3K

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The PI3K/Akt/mTOR pathway is vital in cancer development, with inhibitors showing therapeutic progress.
• Acquired drug resistance limits the clinical application of PI3K inhibitors, necessitating alternative strategies.
• Proteolysis-targeting chimeras (PROTACs) offer a promising therapeutic approach to overcome drug development challenges.

Purpose of the Study:

• To design and synthesize novel small molecular PROTACs targeting PI3K for degradation.
• To evaluate the efficacy of these PROTACs in degrading PI3K and its downstream signaling in liver cancer cells.
• To investigate the anti-proliferative mechanism of the lead PROTAC compound in liver cancer cells.

Main Methods:

• Design and synthesis of a series of small molecular PROTACs.
• Assessment of PI3K degradation and downstream signaling (p-Akt, p-S6K, p-GSK-3β) in HepG2 liver cancer cells.
• Evaluation of cell proliferation inhibition, apoptosis, cell cycle arrest, and autophagy induction by the representative compound.

Main Results:

• Four synthesized compounds demonstrated significant PI3K degradation in HepG2 cells.
• These compounds effectively down-regulated the phosphorylation of Akt, S6K, and GSK-3β.
• The representative compound D inhibited tumor cell proliferation by inducing autophagy, not apoptosis or cell cycle arrest.

Conclusions:

• Small molecular PROTACs can effectively induce PI3K degradation and inhibit downstream signaling.
• PROTAC-mediated PI3K degradation represents a viable therapeutic strategy for liver cancer.
• The lead compound D utilizes autophagy induction as its primary anti-cancer mechanism, offering a novel therapeutic avenue.