In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action




Blevins, Derek J.
Hanley, Ronan
Bolduc, Trevor
Powell, David A.
Gignac, Michael
Walker, Kayleigh
Carr, Mark D.
Hof, Fraser
Wulff, Jeremy E.

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ACS Medicinal Chemistry Letters


The programmed cell death protein 1 (PD-1) signaling axis is among the most important therapeutic targets in modern oncology. Aurigene Discovery Technologies Ltd. (Aurigene) has patented a series of peptidomimetic small molecules derived from the PD-1 protein sequence for use in targeting the interaction between PD-1 and its ligand, PD-L1. We evaluated three of Aurigene’s most potent compounds in SPR binding assays. Our results showed that these compounds—each of which is known to be potently effective in a splenocyte recovery assay—do not directly inhibit the PD-1/PD-L1 interaction nor do they appear to bind to either of the constituent proteins, indicating that another mechanism is at play. As a result of these studies and upon consideration of structural features within the PD-1/PD-L1 complex, we hypothesize that the Aurigene molecules may interact with a currently unknown protein capable of regulating the PD-1 axis.



PD-1, PD-L1, protein-protein interaction inhibitors, SPR


Blevins, D. J., Hanley, R., Bolduc, T., Powell, D. A., Gignac, M., Walker, K., Carr, M. D., Hof, F., & Wulff, J. E. (2019). In vitro assessment of putative PD-1/PD-L1 inhibitors: Suggestions of an alternative mode of action. ACS Medicinal Chemistry Letters, 10(8), 1187-1192.