Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents

Jailani, Ameera B. A.; Bigos, Kamilla J. A.; Avgoustou, Paris; Egan, Joseph L.; Hathway, Robert A; Skerry, Timothy M.; Richards, Gareth O.

doi:10.1080/17460441.2022.2090541

Cited by 4 publications

(4 citation statements)

References 99 publications

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“…AM and the CALCRL-RAMP2 and CALCRL-RAMP3 complexes have been implicated in tumor progression. Selective CALCRL-RAMP2 antagonists have recently been developed as anti-tumor therapeutics, although they are still in the preclinical stage of development ( Avgoustou et al, 2020 ; Jailani et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

et al. 2022

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G protein-coupled receptors (GPCRs) are known to interact with several other classes of integral membrane proteins that modulate their biology and pharmacology. However, the extent of these interactions and the mechanisms of their effects are not well understood. For example, one class of GPCR-interacting proteins, receptor activity-modifying proteins (RAMPs), comprise three related and ubiquitously expressed single-transmembrane span proteins. The RAMP family was discovered more than two decades ago, and since then GPCR–RAMP interactions and their functional consequences on receptor trafficking and ligand selectivity have been documented for several secretin (class B) GPCRs, most notably the calcitonin receptor-like receptor. Recent bioinformatics and multiplexed experimental studies suggest that GPCR–RAMP interactions might be much more widespread than previously anticipated. Recently, cryo-electron microscopy has provided high-resolution structures of GPCR–RAMP–ligand complexes, and drugs have been developed that target GPCR–RAMP complexes. In this review, we provide a summary of recent advances in techniques that allow the discovery of GPCR–RAMP interactions and their functional consequences and highlight prospects for future advances. We also provide an up-to-date list of reported GPCR–RAMP interactions based on a review of the current literature. Significance Statement Receptor activity-modifying proteins (RAMPs) have emerged as modulators of many aspects of G protein-coupled receptor (GPCR)biology and pharmacology. The application of new methodologies to study membrane protein–protein interactions suggests that RAMPs interact with many more GPCRs than had been previously known. These findings, especially when combined with structural studies of membrane protein complexes, have significant implications for advancing GPCR-targeted drug discovery and the understanding of GPCR pharmacology, biology, and regulation.

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Section: Introductionmentioning

confidence: 99%

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

et al. 2022

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“…AM-1 and AM-2 receptors are involved in cancer development; the former also regulates blood pressure. Thus, using AM-1 receptor antagonists as antitumor agents is not possible since these antagonists increase blood pressure [ 357 ]. However, AM-2 receptor antagonists are promising agents as antitumor drugs because they show good pharmacokinetic properties, no serious side-effects, and 1000-fold selectivity over the AM-1 receptor [ 355 , 357 ].…”

Section: Antitumor Therapeutic Strategies Based On the Modulation Of ...mentioning

confidence: 99%

“…Thus, using AM-1 receptor antagonists as antitumor agents is not possible since these antagonists increase blood pressure [ 357 ]. However, AM-2 receptor antagonists are promising agents as antitumor drugs because they show good pharmacokinetic properties, no serious side-effects, and 1000-fold selectivity over the AM-1 receptor [ 355 , 357 ]. In this sense, it is crucial to know which receptors are involved in the effects mediated by the CT/CGRP peptide family in cancer.…”

Section: Antitumor Therapeutic Strategies Based On the Modulation Of ...mentioning

confidence: 99%

“…This finding is important and must be developed as an anticancer strategy, in addition to increasing the knowledge of AM receptor pharmacology. The importance of investigating the residue differences between the AM receptors has also been highlighted to develop selective AM-2 receptor antagonists [ 357 ].…”

Section: Antitumor Therapeutic Strategies Based On the Modulation Of ...mentioning

confidence: 99%

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Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

Sánchez

Rodríguez

Coveñas

2023

Cancers

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The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned.

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Role of LGMN in tumor development and its progression and connection with the tumor microenvironment

Khan

Khan²,

Khan³

et al. 2023

Front. Mol. Biosci.

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Legumain (LGMN) has been demonstrated to be overexpressed not just in breast, prostatic, and liver tumor cells, but also in the macrophages that compose the tumor microenvironment. This supports the idea that LGMN is a pivotal protein in regulating tumor development, invasion, and dissemination. Targeting LGMN with siRNA or chemotherapeutic medicines and peptides can suppress cancer cell proliferation in culture and reduce tumor growth in vivo. Furthermore, legumain can be used as a marker for cancer detection and targeting due to its expression being significantly lower in normal cells compared to tumors or tumor-associated macrophages (TAMs). Tumor formation is influenced by aberrant expression of proteins and alterations in cellular architecture, but the tumor microenvironment is a crucial deciding factor. Legumain (LGMN) is an in vivo-active cysteine protease that catalyzes the degradation of numerous proteins. Its precise biological mechanism encompasses a number of routes, including effects on tumor-associated macrophage and neovascular endothelium in the tumor microenvironment. The purpose of this work is to establish a rationale for thoroughly investigating the function of LGMN in the tumor microenvironment and discovering novel tumor early diagnosis markers and therapeutic targets by reviewing the function of LGMN in tumor genesis and progression and its relationship with tumor milieu.

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Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents

Cited by 4 publications

References 99 publications

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

Role of LGMN in tumor development and its progression and connection with the tumor microenvironment

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