Danielle H Oh, Xiao Ma, Simon J Hogg, Jackson He, Conor Kearney, Daniella Brasacchio, Olivia Susanto, Belinda Maher, Ian G Jennings, Andrea Newbold, Peter Fraser, Emily Gruber, Lev M Kats, Gareth P Gregory, Ricky W Johnstone, Philip E Thompson, Jake Shortt
Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis ( cMYC ) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores...
September 5, 2023: Proceedings of the National Academy of Sciences of the United States of America