Design, Synthesis, and Biological Evaluation of mTOR-Targeting PROTACs Based on MLN0128 and Pomalidomide

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Mechanistic target of rapamycin (mTOR) is a validated anti-tumor target.
• Current mTOR kinase inhibitors face challenges with toxicity.
• Proteolysis targeting chimeras (PROTACs) offer a promising low-dose, low-toxicity therapeutic approach.

Purpose of the Study:

• To design and synthesize novel PROTACs for targeted degradation of mTOR.
• To evaluate the efficacy of these PROTACs in inhibiting cancer cell proliferation.
• To explore the mechanism of action of mTOR-degrading PROTACs.

Main Methods:

• Utilized the mTOR kinase inhibitor MLN0128 as the protein-of-interest ligand.
• Conjugated MLN0128 with pomalidomide via various linker chains to create PROTACs.
• Assessed PROTACs for mTOR inhibitory activity, cell proliferation suppression, and downstream protein inhibition in MCF-7 cells.

Main Results:

• Successfully designed and synthesized novel small molecule PROTACs targeting mTOR.
• PROTAC compounds demonstrated mTOR inhibitory activity and suppressed MCF-7 cell proliferation.
• The representative compound P1 induced autophagy, inhibited mTOR downstream proteins, and reduced cancer cell growth without affecting cell cycle or inducing apoptosis.

Conclusions:

• Novel PROTACs effectively degrade mTOR, offering a potential new therapeutic strategy in oncology.
• The developed PROTACs exhibit anti-cancer effects through mTOR inhibition and autophagy induction.
• This study highlights the potential of PROTAC technology for developing safer and more effective mTOR-targeted cancer therapies.