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On-target and off-target effects of novel orthosteric and allosteric activators of GPR84.

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posted on 16.09.2019, 13:58 by SJ Mancini, ZA Mahmud, L Jenkins, D Bolognini, R Newman, M Barnes, ME Edye, SB McMahon, AB Tobin, G Milligan
Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target.


SM is funded by the Heptares Therapeutics sponsored Opportunities in Receptor Biology for Industrial Translation (ORBIT) scheme. We thank ZAM thanks the Commonwealth Scholarship Commission for financial support. We thank Dr Laurent Saniere (Galapagos NV) for provision of PBS-16671, compounds 104, 107 and [3H]9543 and Dr Trond Ulven for provision of 2-HTP.



Scientific Reports, 2019, 9, Article number: 1861

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/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation


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The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-38539-1



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