OST Catalytic Subunit Redundancy Enables Therapeutic Targeting of N-Glycosylation

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Protein N-glycosylation is crucial for cell surface receptor function, including EGFR.
• The essential nature of N-glycosylation has historically limited its therapeutic targeting in cancer.
• Mammalian oligosaccharyltransferase (OST) has catalytic subunit paralogs, STT3A and STT3B, offering potential for selective inhibition.

Purpose of the Study:

• To explore the chemical biology of OST inhibitors for targeted N-glycosylation inhibition.
• To develop a strategy for limited N-glycosylation inhibition to impact EGFR signaling.
• To identify and evaluate novel OST inhibitors with therapeutic potential in oncology.

Main Methods:

• Synthesis and characterization of small molecules targeting STT3A or STT3B with improved pharmacokinetics.
• In vitro evaluation of OST inhibitor activity and selectivity.
• In vivo testing of lead compounds in patient-derived and TKI-resistant EGFR-mutant lung cancer xenograft models.

Main Results:

• Developed small molecules with pharmacokinetic properties and selectivity for STT3A or STT3B.
• The lead compound, NGI-189, demonstrated efficacy in reducing tumor growth or causing regression in xenograft models.
• NGI-189 exhibited no observable toxicity in preclinical models.

Conclusions:

• Bioavailable OST inhibitors can be developed as effective therapeutic agents for oncology.
• Targeted inhibition of N-glycosylation presents a viable strategy for treating EGFR-mutant lung cancers, including TKI-resistant forms.
• NGI-189 represents a promising drug candidate for further clinical development in cancer therapy.