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