Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Shaabani, Shabnam; Gadina, Louis; Surmiak, Ewa; Wang, Zefeng; Zhang, Bidong; Butera, Roberto; Zarganes‐Tzitzikas, Tryfon; Rodríguez, Ismael; Kocik, Justyna; Magiera‐Mularz, Katarzyna; Skalniak, Łukasz; Dömling, Alexander; Holak, Tad A.

doi:10.3390/molecules27113454

Cited by 6 publications

(2 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…New small molecules targeting PD-L1 are regularly discovered, such as our pyrazolone-type PyrDLones [6] and the pro-drug YPD-30 which was shown recently to bind to PD-L1 and to exhibit significant antitumor activity in vivo [7]. Many other compounds could be cited, all in early preclinical development [8, 9]. These newer molecules remain far from clinical trials at present.…”

Section: Introductionmentioning

confidence: 99%

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

et al. 2023

View full text Add to dashboard Cite

Introduction: The quest for small molecule inhibitors of the PD-1/PD-L1 checkpoint continues in parallel to the extensive development of monoclonal antibodies directed against this immune checkpoint. Drug screening strategies are being set up to identify novel PD-L1 inhibitors. Methods: A virtual screening based on molecular docking with the PD-L1 protein dimer has been performed to identify a new binder. Binding of the identified ligand to PD-L1 has been validated experimentally using a microscale thermophoresis (MST) assay. The cellular effect of the compound was evidenced using a fluorescence resonance energy transfer (FRET) assay based on activation of tyrosine phosphatase SHP-2. Results: We have identified the potent Wnt/β-catenin inhibitor KYA1797K as a weak PD-L1 binder. Molecular docking suggested that the compound can bind to the interface of a PD-L1 dimer, with a geometry superimposable to that of the reference PD-L1 inhibitor BMS-202. The atypical 2-thioxo-4-thiazolidinone motif of KYA1797K, derived from the natural product rhodanine, plays a major role in the interaction with PD-L1. Binding of KYA1797K to recombinant hPD-L1 was validated experimentally, using MST. The drug was found to bind modestly but effectively to hPD-L1. The FRET assay confirmed the weak capacity of KYA1797K to interfere with the activation of SHP-2 upon its interaction with human PD-1. Discussion: Collectively, the data show that KYA1797K could function as a weak modulator of the PD-1/PD-L1 checkpoint. This effect may contribute, at least partially, to the reported capacity of the β-catenin inhibitor to downregulate PD-L1 in cancer cells. The work also underlines the interest to further consider the rhodanine moiety as a chemical motif for the design of new PD-L1 binders.

show abstract

Section: Introductionmentioning

confidence: 99%

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The first PD-L1-targeted inhibitors were proposed in 2017, based on the discovery of the mode of binding to PD-L1 dimer of biphenyl-type compounds from Bristol-Myers Squibb [2,3]. Over the past 6 years, different chemical series of small molecules targeting PD-L1 have been proposed, such as biphenyl-based compounds [4,5], benzamide derivatives [6], benzo-isothiazoles [7], phthalimide derivatives [8] and many others. New molecules are regularly proposed, notably with the support of molecular modeling approaches to guide drug design [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

et al. 2023

View full text Add to dashboard Cite

Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.

show abstract

MPoMA protects against lung epithelial cell injury via p65 degradation

Lee,

Yoon,

et al. 2024

Biomedicine & Pharmacotherapy

View full text Add to dashboard Cite

Biphenyl Ether Analogs Containing Pomalidomide as Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

Cited by 6 publications

References 37 publications

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

A Potential Off-Target Effect of the Wnt/β-Catenin Inhibitor KYA1797K: PD-L1 Binding and Checkpoint Inhibition

Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

MPoMA protects against lung epithelial cell injury via p65 degradation

Contact Info

Product

Resources

About