Abstract |
Small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched to offer anticancer oral treatment modalities. Different small molecules have been designed, such as BMS-202 and BMS-1166 which potently bind to PD-L1, sequestering the protein dimer and thus preventing cancer cells to escape antitumor immune responses. A (top → down) deconvolution of BMS compounds has characterized their central biphenyl unit as the minimal element required for PD-L1 protein binding. On this basis, we searched for approved drugs containing a similar biphenyl unit and endowed with immune modulatory activities. We identified the biphenyl anti-inflammatory drug flurbiprofen (FLB) as a potential candidate for PD-L1 interaction, and then proposed a (bottom → up) convolution to select similar molecules, used in Human, susceptible to engage stable interactions with PD-L1. The hypothesis was tested by molecular modeling using the crystal structure of BMS-202 bound to the PD-L1 dimer. The calculations suggest that both (R) and (S) isomers of FLB can form stable complexes with PD-L1, penetrating deep into the cylindric pocket at the interface of the protein dimer. However, the potential energy of interaction (ΔE) is reduced by ~40% for FLB compared to BMS compounds. Then, we identified three FLB analogues ( diflunisal, CHF-5074 and HCT1026) forming stable complexes with PD-L1. The longer FLB derivative HCT1026 appears as a suitable binder of the PD-L1 dimer, sliding well along the BMS binding cavity. Our approach proposes a new strategy to discover PD-L1-binding small molecules and raises the intriguing possibility that FLB can bind transiently to PD-L1, thus possibly explaining some of its biological effects. Our study opens new perspectives for the use of FLB (and analogs) as an immune modulator in oncology and other therapeutic domains.
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Authors | Christian Bailly, Gérard Vergoten |
Journal | Biochemical pharmacology
(Biochem Pharmacol)
Vol. 178
Pg. 114042
(08 2020)
ISSN: 1873-2968 [Electronic] England |
PMID | 32445869
(Publication Type: Journal Article, Review)
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Copyright | Copyright © 2020 Elsevier Inc. All rights reserved. |
Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- B7-H1 Antigen
- Biphenyl Compounds
- CD274 protein, human
- diphenyl
- Flurbiprofen
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Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(chemistry, metabolism)
- B7-H1 Antigen
(chemistry, metabolism)
- Biphenyl Compounds
(chemistry, metabolism)
- Flurbiprofen
(chemistry, metabolism)
- Humans
- Protein Binding
(physiology)
- Protein Multimerization
(physiology)
- Protein Structure, Secondary
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