Discovery of the DNA-PKcs inhibitor DA-143 which exhibits enhanced solubility relative to NU7441.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a vital role in DNA damage repair and lymphocyte function, presenting a significant target in cancer and immune diseases. Current DNA-PKcs inhibitors are undergoing Phase I/II trials as adjuncts to radiotherapy and chemotherapy in cancer. Nevertheless, clinical utility is limited by suboptimal bioavailability.

DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells.

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known primarily for its function in DNA double-stranded break repair and nonhomologous end joining (NHEJ). However, DNA-PKcs also has a critical yet undefined role in immunity impacting both myeloid and lymphoid cell lineages spurring interest in targeting DNA-PKcs for therapeutic strategies in immune-related diseases. To gain insight into the function of DNA-PKcs within immune cells, we performed a quantitative phosphoproteomic screen in T cells to identify phosphorylation targets of DNA-PKcs.

Knockout of Acinar Enriched microRNAs in Mice Promote Duct Formation But Not Pancreatic Cancer.

The pancreatic acinar-enriched miR-216a, miR-216b and miR-217 are encoded within the miR217HG. These miRNAs have been purported to play a tumor suppressive role as their expression is reduced in both human and mouse pancreatic ductal adenocarcinoma (PDAC). To examine this possibility, we generated individual, germline knockout (KO) mice of miR-216a, miR-216b or miR-217.