Bioactivity-Driven Synthesis of the Marine Natural Product Naamidine J and Its Derivatives as Potential Tumor Immunological Agents by Inhibiting Programmed Death-Ligand 1

Fu, Pan-Pan; Wang, Qun; Zhang, Qing; Jin, Yang; Liu, Jin; Chen, Kaixian; Guo, Yue‐Wei; Liu, Sanhong; Li, Xu‐Wen

doi:10.1021/acs.jmedchem.2c01702

Cited by 3 publications

(1 citation statement)

References 36 publications

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“…The compound displayed antitumor potential in MC 3 8 tumor bearing C 57 BL/6 mice through reduction of PD-L-1 expression and enhancement of tumor infiltrating T-cell immune response. The study provided a direction for new leads discovery from marine products as tumor immunological agents ( 102 ).…”

Section: Non-bms Small Molecules Pd-1/pd-l1 Inhibitorsmentioning

confidence: 99%

Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges

Javed,

Najmi,

Ahsan

et al. 2024

Front. Immunol.

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The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.

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Section: Non-bms Small Molecules Pd-1/pd-l1 Inhibitorsmentioning

confidence: 99%

Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges

Javed,

Najmi,

Ahsan

et al. 2024

Front. Immunol.

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Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

Huang,

Jin,

et al. 2024

Acta Pharmaceutica Sinica B

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Chemoproteomics of Marine Natural Product Naamidine J Unveils CSE1L as a Therapeutic Target in Acute Lung Injury

Gao,

Song,

Yang

et al. 2024

J. Am. Chem. Soc.

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Acute lung injury is a devastating illness characterized by severe inflammation mediated by aberrant activation of macrophages, resulting in significant morbidity and mortality, highlighting the urgent need for novel pharmacological targets and drug candidates. In this study, we identified a novel target for regulating inflammation in macrophages and acute lung injury via chemical proteomics and genetics based on a marine alkaloid, naamidine J (NJ). The structures of NJ-related naamidine alkaloids were first confirmed or revised by a combination of quantum chemical calculations and X-ray diffraction analysis. NJ was found as a potential anti-inflammatory agent by screening our compound library, and CSE1L was identified by chemoproteomics as a main cellular target of NJ to inhibit inflammation in macrophages and protect against acute lung injury. Mechanistically, we demonstrated that NJ directly interacted with CSE1L on the sites of His745 and Phe903 and then inhibited the nuclear translocation and transcriptional activity of transcription factor SP1, thereby suppressing inflammation in macrophages and ameliorating acute lung injury. Taken together, these findings have uncovered a novel pharmacological target for the treatment of acute lung injury and have also provided a potential druggable pocket of CSE1L and a lead compound or an available chemical tool from marine sources for investigating CSE1L function and developing novel drug candidates against acute lung injury.

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Bioactivity-Driven Synthesis of the Marine Natural Product Naamidine J and Its Derivatives as Potential Tumor Immunological Agents by Inhibiting Programmed Death-Ligand 1

Cited by 3 publications

References 36 publications

Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges

Targeting PD-1/PD-L-1 immune checkpoint inhibition for cancer immunotherapy: success and challenges

Discovery of novel small molecules targeting hepatitis B virus core protein from marine natural products with HiBiT-based high-throughput screening

Chemoproteomics of Marine Natural Product Naamidine J Unveils CSE1L as a Therapeutic Target in Acute Lung Injury

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