2017
DOI: 10.1146/annurev-pharmtox-011613-140016
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Challenges and Opportunities in Protease-Activated Receptor Drug Development

Abstract: Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable target… Show more

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Cited by 52 publications
(58 citation statements)
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“…We propose that highly druggable GPCRs are a promising class of targets for metastatic cancer. In fact, several lines of evidence indicate that the GPCR PAR1 is an attractive therapeutic target for advanced breast cancer (11,45). PAR1 confers tumor cell motility, invasiveness, survival and self-renewal in breast cancer and other cancer types (46).…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…We propose that highly druggable GPCRs are a promising class of targets for metastatic cancer. In fact, several lines of evidence indicate that the GPCR PAR1 is an attractive therapeutic target for advanced breast cancer (11,45). PAR1 confers tumor cell motility, invasiveness, survival and self-renewal in breast cancer and other cancer types (46).…”
Section: Discussionmentioning
confidence: 99%
“…Several GPCRs implicated in metastatic cancer, including protease-activated receptor-1 (PAR1), have also proven to be highly druggable (10,11). PAR1 is overexpressed in invasive ductal breast carcinoma but not in normal mammary epithelial tissue (12,13).…”
mentioning
confidence: 99%
“…Apart from controlling coagulation, cellular mechanisms that render TF non‐coagulant also support TF‐FVIIa cell signaling. Coagulation proteases, including TF‐FVIIa, TF‐FVIIa‐FXa, thrombin and activated protein C (aPC), cleave the extracellular domains of PARs and elicit both heterotrimeric G protein and β‐arrestin‐coupled signaling . Although all coagulation proteases can cleave PARs with variable efficiency, protease interactions with specific receptors, their subcellular localization in microdomains, PAR heterodimerization and alternative PAR cleavages result in biased agonism and sometimes opposing downstream cellular responses.…”
Section: Tf‐fviia and Intracellular Signalingmentioning
confidence: 99%
“…[1][2][3][4][5] In the vascular compartment, both PAR-1 and PAR-2 are expressed on endothelial cells (EC), smooth muscle cells, and leukocytes whereas only PAR-1 is expressed on platelets. Cell context-dependent signaling mechanisms that rely on the expression of cofactors, noncanonical cleavage, and their downstream effectors have been described.…”
mentioning
confidence: 99%