Discovery of Novel Small-Molecule Inhibitors to the P-selectin/PSGL-1 Pathway for Enhanced Cancer Immunotherapy

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R. Sevostianov1*, K. Solomon1, R.C. Acurcio2, S. Pozzi1, E. Yeini1, R.C. Guedes2, H.F. Florindo2, R. Satchi-Fainaro1,3,4  
 

1Gray School of Medical Sciences, Tel Aviv University, Israel. Sevostianov@tauex.tau.ac.il  2Research institute for Medicines- iMed.Lisboa, Lisbon, Portugal.  3Sagol School of Neuroscience, Tel Aviv University, Israel.  4Jan Koum center for Nanoscience and Nanotechnology, Tel Aviv University, Israel. * Corresponding Author

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Inhibiting the PD-1/PD-L1 axis has demonstrated significant clinical efficacy in various cancers, but the limited response rates to current monoclonal antibody-based therapies underscore the urgent need for alternative strategies. In a previous study, we employed a transdisciplinary approach combining in silico drug discovery with in vitro, ex vivo, and in vivo experiments to identify novel small molecules capable of inhibiting the PD-1/PD-L1 interactions. By screening a custom prepared library of compounds from readily available sources and the published crystal structure of PD-L1, a structure-based screening with docking followed by filtering the compounds for drug-like properties was performed. Best scoring compounds were further validated in vitro to funnel the compounds with the best inhibitory activity. The hits were found to stimulate human adaptive immune responses and uniquely facilitate extensive T-lymphocyte infiltration into three-dimensional solid tumor models. Additionally, they enhanced cytotoxic T-cell recruitment to the tumor microenvironment in vivo. This new family of small-molecule candidates holds great potential to advance cancer immunotherapy by addressing the current limitations of antibody-based immune checkpoint inhibitors. Following this successful drug discovery campaign, we now turn our attention to P-selectin/P-selectin ligand-1 axis, which we recently discovered as an immune checkpoint in several cancer types. Efforts are now being focused on small-molecule inhibitor development of this axis using the Schrödinger computational platform.