Discovery of New Nanomolar Selective IRAP Inhibitors

Area of Science:

• Biochemistry
• Immunology
• Medicinal Chemistry

Background:

• Insulin-regulated aminopeptidase (IRAP) is an M1 family oxytocinase aminopeptidase.
• IRAP plays a role in MHC-I antigen presentation by trimming peptides.
• Existing IRAP inhibitor chemotypes are limited.

Purpose of the Study:

• To design and optimize novel hydroxamic acid inhibitors of IRAP.
• To explore new chemotypes for IRAP inhibition.
• To investigate the potential of these inhibitors in modulating antigen presentation.

Main Methods:

• Design and synthesis of 5-substituted indole hydroxamic acids.
• In vitro enzymatic assays to determine IRAP inhibitory activity.
• Molecular docking studies to elucidate binding modes.
• Assessment of IRAP-dependent inhibition of antigen cross-presentation.

Main Results:

• A series of hydroxamic acid IRAP inhibitors based on a 5-substituted indole scaffold were developed.
• Compound 43 (BDM_92499) demonstrated single-digit nanomolar potency and selectivity for IRAP.
• Docking studies revealed an original binding mode, with indole substituents and a primary amide crucial for selectivity.
• Several inhibitors effectively suppressed IRAP-dependent antigen cross-presentation.

Conclusions:

• Novel hydroxamic acid inhibitors targeting IRAP have been successfully designed and optimized.
• These compounds represent a promising new chemotype for IRAP inhibition.
• The developed inhibitors offer potential for the development of novel therapeutics targeting IRAP-mediated pathways, including antigen presentation.