CUDC-907, a Dual HDAC and PI3K Inhibitor, Potentially Targets Cancer Cells and The Microenvironment In Hematological Malignancies

Histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K) inhibitors have each emerged as promising anti-cancer therapeutics that may target not only cancer cells but also their microenvironment. We have developed a strategy to simultaneously inhibit HDAC- and PI3K-dependent signaling with a single small molecule, CUDC-907. In this study, we report that CUDC-907 induces apoptosis and G2/M arrest in hematological cancer cells. CUDC-907 also impairs cytokine and chemokine production, in association with inhibition of AKT and STAT phosphorylation. Moreover, we demonstrate that CUDC-907 reduces hypoxia-induced HIF-1a expression in cancer cells and VEGF-induced tube formation in endothelial cells, suggesting potential anti-angiogenic activity. With its integrated HDAC and PI3K inhibitory activity, CUDC-907 may thus offer improved therapeutic benefit through simultaneous suppression of cancer cell proliferation and perturbation of their protective microenvironment. These studies provide support for the clinical development of CUDC-907 in hematological malignancies. A Phase I study in patients with lymphoma or multiple myeloma is ongoing.