Discovery of ICOS-Targeted Small Molecules Using Pharmacophore-Based Screening

Area of Science:

• Drug Discovery and Development
• Immunology
• Computational Chemistry

Background:

• Small molecules offer advantages over monoclonal antibodies (mAbs) for immune checkpoint modulation, including oral bioavailability and improved tumor penetration.
• Inducible co-stimulator (ICOS) and its ligand (ICOS-L) are crucial for T-cell differentiation and B-cell activation.
• Currently, no small molecules are clinically approved as immune checkpoint modulators.

Purpose of the Study:

• To develop and validate a virtual screening strategy for identifying small molecules targeting a novel binding pocket in human ICOS.
• To discover first-in-class small molecule ICOS binders.
• To establish biophysical screening platforms for ICOS-targeted small molecules.

Main Methods:

• Utilized molecular dynamics simulations on ICOS apo-structure and the ICOS/ICOS-L interface to generate 3D pharmacophores.
• Employed virtual screening campaigns based on identified pharmacophores.
• Validated findings using biophysical screening platforms.

Main Results:

• Successfully developed and validated a virtual screening strategy for small molecule ICOS binders.
• Identified a first-in-class small molecule ICOS binder, designated 5P, with a K_D value of 108.08±26.76 μM.
• Confirmed the utility of biophysical screening platforms for evaluating ICOS-targeted small molecules.

Conclusions:

• The developed virtual screening strategy is effective for discovering small molecule ICOS binders.
• The identified small molecule 5P represents a promising starting point for further optimization.
• Future structural optimization of 5P is anticipated to yield high-affinity chemical ligands for ICOS, potentially leading to new cancer immunotherapies.