Nonpeptidic quinazolinone derivatives as dual nucleotide-binding oligomerization domain-like receptor 1/2 antagonists for adjuvant cancer chemotherapy

Ma, Yao; Yang, Jingshu; Wei, Xiduan; Pei, Yukui; Ye, Jingjia; Li, Xueyuan; Si, Guangxu; Tian, Jingyuan; Dong, Yunhui; Liu, Gang

doi:10.1016/j.ejmech.2020.112723

Cited by 4 publications

(7 citation statements)

References 23 publications

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“…Results showed that the NOD‐like receptor signalling pathway was significantly altered in the EV‐HT29‐primed THP‐1 cells (Figure 1b). Moreover, the proinflammatory cytokines interleukin 6 (IL‐6) and tumour necrosis factor‐alpha (TNF‐α), which are upregulated following NOD1 activation (Ma et al., 2020), were highly expressed in THP‐1 cells or BMDMs in the presence of different types of CRC‐EVs (EV‐HT29, EV‐HCT116, and EV‐MC38) but not EV‐CCD18Co (Figure 1c,d).…”

Section: Resultsmentioning

confidence: 99%

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Wei

Pei

et al. 2022

J of Extracellular Vesicle

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Pattern-recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell-derived small extracellular vesicles (EVs). Nucleotidebinding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell-derived EVs (CRC-EVs), to potentiate CRC liver metastasis (CRC-LM), remain poorly understood. Here, we demonstrate that CRC-EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1-activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1-deficient mice exhibit reduced metastasis following CRC-EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine-5′-triphosphate (GTP)ase, is delivered by CRC-EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC-LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC-LM. Our findings suggest that CRC-EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC-LM.

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Section: Resultsmentioning

confidence: 99%

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Wei

Pei

et al. 2022

J of Extracellular Vesicle

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“…Ma et al obtain a novel quinazolinone derivative as a cytosolic protein receptor 1 and 2 (NOD1/2) dual antagonist [ 64 ]. NOD1 and NOD2 are a key target for immunotherapy due to the presence of a nucleotide-binding oligomerization domain that is an important component of the innate immune system [ 65 , 66 , 67 , 68 , 69 , 70 ].…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

“…NOD1 and NOD2 are a key target for immunotherapy due to the presence of a nucleotide-binding oligomerization domain that is an important component of the innate immune system [ 65 , 66 , 67 , 68 , 69 , 70 ]. Antagonism of both NOD1 and NOD2 signaling guarantees the effectiveness of adjuvant cancer treatment [ 64 ]. Compound ( 19 ) was not the most active against both NOD1-and NOD2 in HEK293 cells with an IC 50 = 1.13 μM and 0.77 μM, respectively; however, it possessed the highest metabolic stability.…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

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Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Kozyra

Pitucha

2022

IJMS

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The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013–2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure–Activity–Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.

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“…Given that only slight changes to the dipeptide moiety of MDP are permitted, all NOD2 agonists share the predominantly peptide structure of MDP, which is prone to metabolic instability and rapid elimination [ 21 , 22 ]. Similarly, while dual NOD1/2 antagonists, such as benzodiazepine [ 18 ], benzofused five-membered sultam [ 23 ], quinazoline [ 24 ], and indole [ 25 ] derivatives have been reported, the only NOD2 selective antagonists discovered to date are based on the benzimidazole structure of GSK669 ( Figure 1 , compound GSK669 and its derivative SG84 [ 26 ]), which was first discovered by an HTS campaign [ 27 ]. Therefore, novel scaffolds capable of modulating the activity of NOD2 are required.…”

Section: Introductionmentioning

confidence: 99%

Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening

Guzelj

Tomašič

2022

Biomolecules

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an innate immune pattern recognition receptor responsible for the recognition of bacterial peptidoglycan fragments. Given its central role in the formation of innate and adaptive immune responses, NOD2 represents a valuable target for modulation with agonists and antagonists. A major challenge in the discovery of novel small-molecule NOD2 modulators is the lack of a co-crystallized complex with a ligand, which has limited previous progress to ligand-based design approaches and high-throughput screening campaigns. To that end, a hybrid docking and pharmacophore modeling approach was used to identify key interactions between NOD2 ligands and residues in the putative ligand-binding site. Following docking of previously reported NOD2 ligands to a homology model of human NOD2, a structure-based pharmacophore model was created and used to virtually screen a library of commercially available compounds. Two compounds, 1 and 3, identified as hits by the pharmacophore model, exhibited NOD2 antagonist activity and are the first small-molecule NOD2 modulators identified by virtual screening to date. The newly identified NOD2 antagonist scaffolds represent valuable starting points for further optimization.

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Nonpeptidic quinazolinone derivatives as dual nucleotide-binding oligomerization domain-like receptor 1/2 antagonists for adjuvant cancer chemotherapy

Cited by 4 publications

References 23 publications

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Novel Scaffolds for Modulation of NOD2 Identified by Pharmacophore-Based Virtual Screening

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