Discovery of ICOS-targeted small molecules using affinity selection mass spectrometry screening

Area of Science:

• Immunology
• Medicinal Chemistry
• Biochemistry

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.
• Current ICOS modulators are biologics, creating a need for small-molecule alternatives.

Purpose of the Study:

• To discover novel small molecules targeting the ICOS pathway.
• To identify a lead compound for developing small-molecule ICOS modulators.

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:

• Identified compound 9 with an ICOS/ICOS-L inhibitory profile (IC₅₀ = 29.38 ± 3.41 μM).
• ASMS screening successfully identified small molecules targeting immune checkpoints.
• MD simulations revealed the critical role of an ortho-hydroxy group in compound 9 for ICOS binding via hydrogen bond formation.

Conclusions:

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