This technology includes the synthesis and use of novel PI3K and HDAC dual inhibitors for the treatment of several cancers. Phosphatidylinositol 3-kinase (PI3K) is activated in many human cancers, and inhibition of these kinases is an established cancer treatment. Histone deacetylases (HDACs) are key regulators of the cell cycle that function through regulating expression of tumor suppressors (p21 and p27), c-Myc and cyclin D1. HDAC inhibition is an emerging therapeutic approach for the treatment of several cancers. Recent work has reported that the combination of an HDAC inhibitor and a kinase inhibitor overcomes kinase inhibitor resistance and induces apoptosis in human solid cancers in a synergistic manner.
The HDAC/PI3K dual inhibitors of this invention are expected to have synergistic anti-tumor activity. In addition, they also could address issues like resistance and insufficient efficacy associated with PI3K and HDAC inhibitors. These compounds potentially could be developed into useful therapies for certain cancers, e.g. leukemia, lung cancer, pancreatic cancer and melanoma.
PI3K and HDAC inhibitors are important cancer therapeutics. Several of them have been approved. But both classes of inhibitors suffer from two major limitations, insufficient efficacy and developed resistance. There is strong evidence in the literature that, simultaneous inhibition of both PI3K and HDAC would address both these limitations. The PI3K/HDAC dual inhibitor compounds of this invention potentially could be developed into useful cancer therapeutics, giving better efficacy, and a better therapeutic window than single inhibitors, while avoiding developed resistance.