Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation

Pan, Chenghao; Yang, Haiyan; Lü, Yang; Hu, Shengquan; Wu, Yizhe; He, Qiaojun; Dong, Xiaowu

doi:10.1016/j.ejmech.2021.113170

Cited by 39 publications

(23 citation statements)

References 90 publications

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“…Cellular Thermal Shift Assay. In brief, after 5 × 10 6 LLC cells were treated with DMSO or B2 for 2 h, cells were incubated and equally divided into 10 parts, and each part was heated for 3 min under different temperatures (43,46,49,52,55,58,61,64,67, and 70 °C) by using a PCR instrument and then kept at 80 °C for 12 h and room temperature for 5 min for 2 cycles. After that, cell lysates were extracted by centrifugation at 20,000g for 20 min.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…So far, no small-molecule PD-1/PD-L1 inhibitors have been approved for use in clinical settings. Although many reported inhibitors showed good biochemical inhibitory activity, , only three compounds have been reported to show anticancer activity in vivo to date. ,, Therefore, there exists a continuing need for the development of new small-molecule PD-1/PD-L1 inhibitors with potent efficacy in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo

et al. 2021

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Two series of novel o-(biphenyl-3-ylmethoxy)nitrophenyl compounds (A1–31 and B1–17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo

et al. 2021

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“…Besides, mAb drugs are expensive, complex to produce, and difficult to store and transport. Therefore, how to use the PD1/PDL1 signaling pathway to develop simple and efficient non-monoclonal antibody treatment strategy is the focus of our current work ( Pan et al, 2021 ).…”

Section: Mechanism Of Action and Treatment Of Pd1/pdl1 Inhibitorsmentioning

confidence: 99%

PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy

et al. 2021

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Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. In this paper, we reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy. We hope that in the future, promising combination therapy regimens can be developed to allow immunotherapeutic tools to play an important role in tumor treatment. We also discuss the safety issues of immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings.

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“…Since that time, besides a few exceptions, studies on small molecules targeted at PD-L1 have mainly focused on the SAR analysis of the biphenyl core. Extensive work on biphenyl molecules has resulted in a huge number of publications and patents appearing in the last 5 years [8,9]. However, only a handful of these molecules have progressed to clinical trials [2].…”

Section: Introductionmentioning

confidence: 99%

“…The second group of PD-L1 targeting non-antibody agents consists of macrocyclic peptides, with several notable examples disclosed by Bristol Myers Squibb [10,11]. Peptidomimetics that interfere with the PD-1/PD-L1 immune checkpoint have also been proposed as an alternative to small-molecule and peptide compounds [9].…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

Surmiak

Magiera‐Mularz

Musielak

et al. 2021

IJMS

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Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

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Recent advance of peptide-based molecules and nonpeptidic small-molecules modulating PD-1/PD-L1 protein-protein interaction or targeting PD-L1 protein degradation

Cited by 39 publications

References 90 publications

Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo

Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo

PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy

PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

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