In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action
Date
2019
Authors
Blevins, Derek J.
Hanley, Ronan
Bolduc, Trevor
Powell, David A.
Gignac, Michael
Walker, Kayleigh
Carr, Mark D.
Hof, Fraser
Wulff, Jeremy E.
Journal Title
Journal ISSN
Volume Title
Publisher
ACS Medicinal Chemistry Letters
Abstract
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.
Description
Keywords
PD-1, PD-L1, protein-protein interaction inhibitors, SPR
Citation
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. https://doi.org/10.1021/acsmedchemlett.9b00221