Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues
Paul B Noto 1, Timothy W Sikorski 2, Francesca Zappacosta 3, Craig D Wagner 3, Rocio Montes de Oca 4, Matthew E Szapacs 2, Roland S Annan 3, Yan Liu 5, Charles F McHugh 6, Helai P Mohammad 5, Steven P Piccoli 4 7, Caretha L Creasy 5

Arginine methylation continues to be acknowledged as a publish-translational modification with pleiotropic effects that span from regulating transcription to metabolic processes that lead to aberrant cell proliferation and tumorigenesis. It has introduced significant focus on the introduction of therapeutic strategies targeted at blocking the game of protein arginine methyltransferases (PRMTs), which catalyze the development of numerous methylated arginine products on a multitude of cellular substrates. GSK3368715 is really a small molecule inhibitor of type I PRMTs presently in clinical development. Here, we assess the aftereffect of type I PRMT inhibition on arginine methylation in normal human peripheral bloodstream mononuclear cells and apply an extensive proteomic method of identify type I PRMT substrates. The work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) like a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were designed to identify and quantitate alterations in methylation of specific arginine residues on hnRNP-A1. This led to the event and validation of novel MS and immune assays helpful for that assessment of GSK3368715 caused pharmacodynamic effects in bloodstream and tumors that may be put on GSK3368715 numerous studies.