We have been designing and synthesizing novel PI3K and HDAC dual inhibitors. Using a matrix approach to screen compounds across a range of concentrations, we have discovered several molecules that inhibit both PI3K and HDAC with single digit nanomolar potency. Several selected compounds have been tested in the NCI60 cell line panel, showing anti-proliferation and cell-killing activity in several cell lines. Selected compounds were examined in cell-based target engagement assays, confirming that the dual inhibitors engage both PI3K-delta and HDAC6 in cells. We have successfully developed a nano-particle formulation for one of our front-runner compounds. Formulation for another promising compound is ongoing. Once these two formulations are in-hand, we will evaluate them in in vitro and in vivo assays.
