Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy

Wang, Kaizhen; Zhang, Xiangyu; Cheng, Yao; Qi, Zhihao; Ye, Ke; Zhang, Kuojun; Jiang, Sheng; Liu, Yi; Xiao, Yibei; Wang, Tianyu

doi:10.1021/acs.jmedchem.3c01534

Cited by 8 publications

(3 citation statements)

References 30 publications

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“…Additionally, the molecular mechanism of their action was determined, which usually involves PD-L1 homodimerization [ 22 ]. This was confirmed by X-ray crystal structure analyses of several biaryl-based small molecules/PD-L1 dimer co-crystals [ 23 , 24 , 25 ]. The observed twofold symmetry of the homodimer became the basis for the design of the first symmetrical inhibitors.…”

Section: Introductionmentioning

confidence: 71%

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Klimek,

Kruc,

Ceklarz

et al. 2024

Molecules

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The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the protein.

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Section: Introductionmentioning

confidence: 71%

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Klimek,

Kruc,

Ceklarz

et al. 2024

Molecules

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“…Although small-molecule inhibitors are expected to circumvent the drawbacks of antibody drugs, their development has lagged far behind. Current small-molecule inhibitors generally exhibit poor PK properties (e.g., compound NP-19, F = 5%; compound P18, F = 12%; compound B9, F = 1.6%; compound 7, F = 22%; compound 12, F = 21.6%; etc . ), which may be due to the high hydrophobicity of these molecules .…”

Section: Conclusion and Perspectivesmentioning

confidence: 99%

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Wang,

Yuan,

Liao

et al. 2024

J. Med. Chem.

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Targeting the programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has evolved into one of the most promising strategies for tumor immunotherapy. Thus far, multiple monoclonal antibody drugs have been approved for treating a variety of tumors, while the development of small-molecule PD-1/PD-L1 inhibitors has lagged far behind, with only a few small-molecule inhibitors entering clinical trials. In addition to antibody drugs and small-molecule inhibitors, reducing the expression levels of PD-L1 has attracted extensive research interest as another promising strategy to target the PD-1/PD-L1 pathway. Herein, we analyze the structures and mechanisms of molecules that reduce PD-L1 expression and classify them as degraders and downregulators according to whether they directly bind to PD-L1. Moreover, we discuss the potential prospects for developing PD-L1-targeting drugs based on these molecules. It is hoped that this perspective will provide profound insights into the discovery of potent antitumor immunity drugs. ■ SIGNIFICANCEReducing PD-L1 expression has been considered as a promising strategy to modulate the PD-1/PD-L1 pathway, which has attracted continuous research interests. This perspective focuses on analyzing the molecules capable of reducing PD-L1 expression and classifies them as degraders and down-regulators according to whether they directly bind to PD-L1. Additionally, it provides deep insights into the rational design strategies and challenges for the development of PD-L1 degraders as well as PD-L1-based combination therapies and multitarget drugs.

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“…Among them, biphenyl PD-L1 inhibitors that block the PD-1/PD-L1 interaction by binding to PD-L1 have gained more attention due to their outstanding inhibitory activity and clear mechanism of action. − Since the disclosure of a series of biphenyl compounds (e.g., BMS-37, BMS-202, and BMS-1166, Figure ) as PD-L1 inhibitors by Bristol Myers Squibb (BMS) in 2015, numerous biphenyl-based PD-L1 inhibitors have been reported . Notably, IMMH-010 (Phase I, Figure ) developed by Chasesun and MAX-10181 (Phase I, Figure ) developed by Maxinovel are currently undergoing clinical trials. , In the continuing research, based on the characteristics of the binding pocket of the dimerized PD-L1 with inhibitors, a class of symmetrical biphenyl PD-L1 inhibitors were reported, , such as LH130 (Figure ) designed by Hu’s group and INCB086550 (Phase II, Figure ) disclosed by Incyte, , which could occupy a larger space in the binding pocket and also exhibited outstanding inhibition on the PD-1/PD-L1 interaction.…”

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confidence: 99%

Design, Synthesis, and Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists

Wu,

Li,

Liu

et al. 2024

ACS Med. Chem. Lett.

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Small-molecule inhibitors targeting programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions can compensate for the shortcomings of antibodybased inhibitors and have attracted considerable attention, some of which have already entered clinical trials. Herein, based on our previous study on small-molecule PD-L1 inhibitors, we reported a series of 8-(o-tolyl)quinazoline derivatives by the skeleton merging strategy. Homogenous time-resolved fluorescence (HTRF) assay against PD-1/PD-L1 interaction identified compound A5, which showed the most potent inhibition with an IC 50 value of 23.78 nM. Meanwhile, based on the results of HTRF assay, the structure− activity relationships (SARs) of the tail were focused on. Cellbased PD-1/PD-L1 blockade assay further revealed that A5 significantly blocked the PD-1/PD-L1 interaction at 1.1 μM in the co-culture system of Jurkat-NFAT-PD-1 cells and Hep3B-OS8-hPD-L1 cells with no significant cytotoxicity on Jurkat cells. Moreover, the proposed binding mode of A5 was investigated by a docking analysis. These results indicate that compound A5 is a promising lead compound that deserves further investigation.

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Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy

Cited by 8 publications

References 30 publications

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Reducing PD-L1 Expression by Degraders and Downregulators as a Novel Strategy to Target the PD-1/PD-L1 Pathway

Design, Synthesis, and Evaluation of 8-(o-Tolyl)quinazoline Derivatives as Small-Molecule PD-1/PD-L1 Antagonists

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