A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [scRNA-seq]

We hypothesised that PI3K and BET inhibition would synergise in the context of MYC-dysregulation and overcome resistance to single-target inhibition. We then synthesised a series of chimeric molecules linking BET- and PI3K-selective pharmacophores, including our lead molecule, 18D(S). RNA-Seq profiling following acute 18D(S) treatment demonstrated robust transcriptional modulation with concomitant BET and PI3K inhibitory signatures. Our data provides proof-of-concept for the design of potent PI3K- and BET-inhibitors, providing 'synergy in a single molecule'. Overall design: The OPM2 multiple myeloma cell line was treated in vitro with 500 nM each of JQ1, BKM120, JQ1+BKM120, 18DS, or vehicle for 2 hours prior to single-cell RNA-sequencing (scRNA-seq).