Abstract Number: PB0966
Meeting: ISTH 2021 Congress
Background: The C-type lectin-like receptor-2 (CLEC-2) is a platelet receptor for the endogenous ligand Podoplanin. This interaction contributes to a number of pathophysiological roles, such as lymphangiogenesis, preservation of blood and lymphatic vessel integrity, organ development and tumour metastasis. Activation of CLEC-2 leads to the phosphorylation of its cytoplasmic hemITAM domain and initiates a signalling cascade involving Syk and PLCγ2.
Aims: The aim of this study was to identify a small-molecule inhibitor of the CLEC-2-Podoplanin interaction and to characterise their effect on human platelet activation.
Methods: AlphaScreen-based high-throughput screening identified a small-molecule inhibitor of the CLEC-2-Podopolanin interaction. Light transmission aggregometry, platelet spreading and phosphorylation assays were used to evaluate the effect of the small molecule on CLEC-2 mediated platelet activation.
Results: 18,476 small molecules were screened resulting in 14 candidates. Following the secondary screening, one small molecule (MAS9) was taken forward for further characterisation. 20 µM of MAS9 inhibited platelet aggregation in response to the CLEC-2 agonist Rhodocytin. MAS9 dose-dependently inhibited platelet spreading and adhesion on immobilized Podoplanin and Rhodocytin. 30 µM MAS9 inhibited the phosphorylation of Syk, PLCγ2 and Src in platelets activated by Rhodocytin. Partial inhibition of GPVI mediated aggregation and spreading was observed but MAS9 did not impact GPVI mediated phosphorylation.
Conclusions: MAS9 potently inhibits CLEC-2-mediated aggregation, platelet spreading and phosphorylation, showing selectivity on CLEC-2 inhibition over GPVI. Further pharmacological and functional experiments will be carried out to establish the potential of MAS9 as a lead compound to identify a novel anti-platelet drug with therapeutic effects in thrombosis and cancer.
To cite this abstract in AMA style:Sowa MA, van Groningen J, Di Y, Gibbins JM, García Á, Pollitt AY. MAS9 – A Novel Small Molecule Inhibitor of the CLEC-2-Podoplanin Interaction [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/mas9-a-novel-small-molecule-inhibitor-of-the-clec-2-podoplanin-interaction/. Accessed November 27, 2021.
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