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

Abstract

AbstractThere are currently no small molecules clinically approved as immune checkpoint modulators. Besides possessing oral bioavailability, cell‐penetrating capabilities and enhanced tumor penetration compared to monoclonal antibodies (mAbs), small molecules are amenable to pharmacokinetic optimization, which allows adopting flexible dosage regimens that may avoid immune‐related adverse events associated with mAbs. The interaction of inducible co‐stimulator (ICOS) with its ligand (ICOS‐L) plays key roles in T‐cell differentiation and activation of T‐cell to B‐cell functions. This study represents the development and validation of a virtual screening strategy to identify small molecules that bind a novel druggable binding pocket in human ICOS. We used a lipophilic canyon in the apo‐structure of ICOS and the ICOS/ICOS‐L interface individually as templates for molecular dynamics simulation to generate 3D pharmacophores subsequently used for virtual screening campaigns. Our strategy was successful finding a first‐in‐class small molecule ICOS binder (5P, KD value=108.08±26.76 μM) and validating biophysical screening platforms for ICOS‐targeted small molecules. We anticipate that future structural optimization of 5P will result in the discovery of high affinity chemical ligands for ICOS.