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

被引：24

作者：

Blevins, Derek J. ^{[1
]}

Hanley, Ronan ^{[1
]}

Bolduc, Trevor ^{[1
]}

Powell, David A. ^{[2
]}

Gignac, Michael ^{[1
]}

Walker, Kayleigh ^{[3
]}

Carr, Mark D. ^{[3
]}

Hof, Fraser ^{[1
]}

Wulff, Jeremy E. ^{[1
]}

机构：

[1] Univ Victoria, Dept Chem, POB 3065 STN CSC, Victoria, BC V8W 3V6, Canada

[2] Incept Sci Canada, 210-887 Great Northern Way, Vancouver, BC V5T 4T5, Canada

[3] Univ Leicester, Leicester Inst Struct & Chem Biol, Leicester, Leics, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 08期

基金：

加拿大自然科学与工程研究理事会;

关键词：

PD-1; PD-L1; protein-protein interaction inhibitors; SPR; SMALL MOLECULES; PD-L1; CANCER; EXPRESSION; DOCETAXEL; OVEREXPRESSION; ASSOCIATION; ANTIBODIES; NIVOLUMAB; PATHWAY;

D O I：

10.1021/acsmedchemlett.9b00221

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Aurigenes 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.

引用

页码：1187 / 1192

页数：11

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