Discovery of ICOS-Targeted Small Molecules Using Affinity Selection Mass Spectrometry Screening

Area of Science:

• Immunology
• Pharmacology
• Medicinal Chemistry

Background:

• Inducible T cell co-stimulator (ICOS) is a positive immune checkpoint receptor on activated T cells.
• ICOS modulation shows clinical benefits in cancer and autoimmune diseases, but current treatments are limited to biologics.
• There is a lack of small molecule modulators targeting ICOS.

Purpose of the Study:

• To discover novel small molecules targeting the ICOS immune checkpoint.
• To identify and characterize small molecule inhibitors of the ICOS/ICOS-L interaction.

Main Methods:

• Affinity selection mass spectrometry (ASMS) screening of 15,600 molecules for ICOS binding.
• Structure-activity relationship (SAR) studies.
• Molecular dynamic (MD) simulations.

Main Results:

• The first reported ASMS screening for small molecules targeting immune checkpoints.
• Compound 9 identified as a promising ICOS/ICOS-L inhibitor (IC50=29.38±3.41 μM).
• An ortho-hydroxy group on Compound 9 is critical for ICOS binding, stabilizing interaction via hydrogen bonds with glycan residuals.

Conclusions:

• This study validates a promising small molecule inhibitor for the ICOS/ICOS-L interaction.
• The findings pave the way for developing more potent ICOS modulators through future modifications.
• This work establishes ASMS as a viable method for discovering small molecule immune checkpoint inhibitors.