Context-dependent translation inhibition as a cancer therapeutic modality

Area of Science:

• Molecular Biology
• Medicinal Chemistry
• Oncology

Background:

• Bacterial antibiotics targeting the ribosomal peptidyl transferase center (PTC) exhibit context-dependent inhibition of protein synthesis.
• This context-dependent inhibition has not been previously documented for inhibitors of the human ribosome PTC.

Purpose of the Study:

• To design and synthesize novel small molecules (interdictors) that selectively inhibit the human ribosome PTC in a context-dependent manner.
• To investigate the mechanism of action and anti-tumor efficacy of these interdictors.

Main Methods:

• Structure-based drug design was employed to guide the synthesis of interdictors.
• Interactions with nascent polypeptide chains and ribosomal RNA were analyzed.
• Impact on ribosome surveillance pathways, including the ribotoxic stress response, was assessed.
• Anti-tumor activity was evaluated in a mouse xenograft model of triple-negative breast cancer.

Main Results:

• Novel PTC-binding, context-dependent inhibitors (interdictors) of the human ribosome were successfully synthesized.
• These compounds induce structural rearrangements in the nascent polypeptide chain and ribosomal RNA.
• Interdictors differentially modulate ribosome surveillance pathways.
• Oral administration of interdictors demonstrated anti-tumor activity in a triple-negative breast cancer model.

Conclusions:

• Targeting oncogenic dependency factors via context-dependent translation inhibition represents a viable therapeutic strategy.
• Interdictors offer a potential small molecule therapeutic modality for difficult-to-treat cancers, including triple-negative breast cancer.