(1090-C) Development of Tumor and Blood Pharmacodynamic Assays to Support Development of IACS-53152, a Protein Arginine Methyltransferase 1 Inhibitor
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Protein arginine methyltransferase 1 (PRMT1) catalyzes the asymmetric di-methylation of arginine residues in histone and non-histone proteins. Recently, pancreatic ductal adenocarcinoma (PDAC) was shown to be dependent on PRMT1 (1). PDAC is a very aggressive cancer with limited therapeutic options, which prompted our medicinal chemistry efforts to discovery of IACS-53152, a potent and selective PRMT1 inhibitor with compelling in vivo activity in PDAC xenograft models. To support IACS-53152 development, we validated and established tumor and blood pharmacodynamic assays to examine pharmacokinetic and pharmacodynamic (PK/PD) relationship of IACS-53152.
Accumulation of global arginine monomethylation (MMA) within the glycine-arginine rich domains has been defined by genetic studies as selective PRMT1 target engagement biomarker. Moreover, mass spectrometry-based proteomics approaches have identified H3, hnRNPA1, FUS, EWS, and TAF-15 as PRMT1 substrates in PDAC cell lines (1). Following reagents validation, we implemented robust assays to quantify site specific asymmetric dimethylation of TAF15 and hnRNPA1 as tumor PD markers. Accumulation of global MMA was selected as peripheral (PBMCs) PD marker for PRMT1 inhibition. We have studied the pharmacokinetic and pharmacodynamic (PK/PD) relationship of PRMT1 inhibitors and demonstrated tumor target engagement after 4 days in PANC1 subcutaneous xenograft model in vivo.