Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions

Kim, Eunhye; Kawamoto, Masuki; Dharmatti, Roopa; Kobatake, Eiry; Ito, Yoshihiro; Miyatake, Hideyuki

doi:10.3390/ijms21103639

Cited by 9 publications

(5 citation statements)

References 48 publications

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“…Bristol-Myers Squibb (BMS) has disclosed the patent claim with structures of a number of BMS compounds, which are the potential inhibitors of the PD-1/ PD-L1 pathway. One of the BMS compounds, BMS-8, binds to PD-L1 directly and induces formation of PD-L1 homodimers, which in turn prevents PD-1 interaction in previous studies (42,43). Here, we optimized the sequence to synthesize the SP-PROTAC.…”

Section: Discussionmentioning

confidence: 99%

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

et al. 2023

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IntroductionImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that target immune checkpoints that suppress immune cell activity. Low efficiency and high resistance are currently the main barriers to their clinical application. As a representative technology of targeted protein degradation, proteolysis-targeting chimeras (PROTACs) are considered to have potential for addressing these limitations.MethodsWe synthesized a stapled peptide-based PROTAC (SP-PROTAC) that specifically targeted palmitoyltransferase ZDHHC3 and resulted in the decrease of PD-L1 in human cervical cancer cell lines. Flow cytometry, confocal microscopy, protein immunoblotting, Cellular Thermal Shift Assay (CETSA), and MTT assay analyses were conducted to evaluate the effects of the designed peptide and verify its safety in human cells.ResultsIn cervical cancer celllines C33A and HeLa, the stapled peptide strongly downregulated PD-L1 to < 50% of baseline level at 0.1 μM. DHHC3 expression decreased in both dosedependentand time-dependent manners. MG132, the proteasome inhibitor, can alleviate the SP-PROTAC mediated degradation of PD-L1 in human cancer cells. In a co-culture model of C33A and T cells, treatment with the peptide induced IFN-γ and TNF-α release in a dose-dependent manner by degrading PD-L1. These effects were more significant than that of the PD-L1 inhibitor, BMS-8.ConclusionsCells treated with 0.1 μM of SP-PROTAC or BMS-8 for 4 h revealed that the stapled peptide decreased PD-L1 more effectively than BMS-8. DHHC3-targeting SP-PROTAC decreased PD-L1 in human cervical cancer more effectively than the inhibitor BMS-8.

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Section: Discussionmentioning

confidence: 99%

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

et al. 2023

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“…The occurrence of pyroptosis in vivo indicates the prospective value of pyroptosis in regulating tumorigenesis and inducing pyroptosis has been designed to eliminate tumors. Small molecule drugs like BMS-8 and BMS-202 are crucial in tumor immunotherapy by inhibiting PD-1 and PD-L1 interaction ( 36 , 37 ). Recently, Yuan et al.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis quantifies pyroptosis in the immune microenvironment of HBV-related hepatocellular carcinoma

Zhang

et al. 2022

Front. Immunol.

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Pyroptosis, a way of pro-inflammatory death, plays a significant part in the tumor microenvironment (TME). A recent study has shown that the hepatitis C virus changes the TME by inducing pyroptosis against hepatocellular carcinoma (HCC). However, compared to TME in hepatitis C virus-infected HCC, the exploration of immune characteristics and response to immunotherapy associated with the pyroptosis phenotype is still insufficient in hepatitis B virus-related HCC (HBV-HCC). Our study constructed pyroptosis-score (PYS) via principal-component analysis (PCA) to unveil the link between pyroptosis and tumor immunity in 369 HBV-HCC patients. Compared with the low-PYS group, subjects with higher PYS were associated with poor prognosis but were more susceptible to anti-PD-L1 treatment. In addition, we found that PYS can serve independently as a prognostic factor for HBV-HCC, making it possible for us to identify specific small molecule drugs with a potential value in inhibiting tumors via targeting pyroptosis. Also, the target genes predicted by the Weighted gene co-expression network analysis (WGCNA) and pharmacophore model were enriched in the HIF-1 signaling pathway and NF-kB transcription factor activity, which were related to the mechanism of inflammation-driven cancer. The PYS is extremely important in predicting prognosis and responses to immunotherapy. New treatment strategies for inflammation-driven cancers may be found by targeting pyroptosis.

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“…More recently, Kim et al. 19 designed and synthesized a series of BMS-8 derivatives. The results showed that the IC 50 value of the most potent biphenyl-conjugated bromotyrosine increased by five times compared with the BMS-8 compound.…”

Section: Introductionmentioning

confidence: 99%

“…According to the linear relationship between the substitutions and the activities, the research also showed that the pharmacophore elements at R2, R4, R6, and R7 had a significant effect on the activities of BMS inhibitors. More recently, Kim et al 19 designed and synthesized a series of BMS-8 derivatives. The results showed that the IC 50 value of the most potent biphenylconjugated bromotyrosine increased by five times compared with the BMS-8 compound.…”

Section: Introductionmentioning

confidence: 99%

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Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study

et al. 2020

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Although mAbs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway have achieved remarkable therapeutic potential against multiple types of cancer, it is still of great interest for researchers to develop small-molecule PD-1/PD-L1 inhibitors without the mAb-related disadvantages of no oral bioavailability and poor solid tumor penetration. However, targeting the PD-1/PD-L1 pathway with small molecules is normally considered challenging because of the flat and large interaction surface of the PD-1/PD-L1 complex. In this paper, a total of 2558 PD-1/PD-L1 inhibitors were compiled from recent patents and literatures and then used for exploring the chemical space and structural features of PD-1/PD-L1 inhibitors by partial least-squares discriminant analysis. The results showed that intramolecular H bond, amphotericity indices, radius of gyration, nonbond electrostatic energy, fractional van der Waals surface area of H-bond donors, octanol–water partition coefficient, and molecular weight are the seven key features discriminating the PD-1/PD-L1 inhibitors from noninhibitors, with the prediction accuracy larger than 0.90. Based on the seven crystal structures of the PD-L1 dimer complexed with the patent Bristol Myers Squibb (BMS) inhibitors, the feasibility of molecular docking for this unconventional binding pocket was further investigated. The results showed that the ensemble-based flexible docking protocol can reproduce the near-native binding conformations of the BMS inhibitors with a strong correlation between the IC 50 values and ligand–receptor interaction energies ( R = 0.81). In general, this paper delineates, for the first time, the characteristic features of the PD-1/PD-L1 inhibitors as well as a high-quality flexible docking strategy for the unconventional binding pocket of the PD-L1 dimer.

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Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions

Cited by 9 publications

References 48 publications

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

Genomic analysis quantifies pyroptosis in the immune microenvironment of HBV-related hepatocellular carcinoma

Partial Least-Squares Discriminant Analysis and Ensemble-Based Flexible Docking of PD-1/PD-L1 Inhibitors: A Pilot Study

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