Role of Hydroxamate-Based Histone Deacetylase Inhibitors (Hb-HDACIs) in the Treatment of Solid Malignancies

Abstract

Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms.

Figure 1

Chemical structures of Hb-HDACIs. Three different Hb-HDACIs, vorinostat, belinostat and panobinostat, are depicted in their planar formulae. The hydroxamic acid group, which characterizes this class of HDACIs, is represented in the square. It is responsible for the binding of these compounds to the zinc ion located into the catalytic domain of the enzyme.

Figure 2

General structure of Hb-HDACI and its interaction with the HDAC enzyme. Hb-HDACIs contain three distinct structural motifs: a zinc binding group represented by the hydroxamic acid, an aliphatic linker that occupies the cavity of the HDAC enzyme, and a surface recognition cap group. The hydroxamic acid interacts with the zinc ion and the histidine 142 in the HDAC pocket inhibiting the enzyme activity.