Profile of panobinostat and its potential for treatment in solid tumors: an update

Abstract

The histone deacetylase (HDAC) inhibitors have emerged as novel therapies for cancer. Panobinostat (LBH 589, Novartis Pharmaceuticals) is a pan-deacetylase inhibitor that is being evaluated in both intravenous and oral formulations across multiple tumor types. Comparable to the other HDACs, panobinostat leads to hyperacetylation of histones and other intracellular proteins, allowing for the expression of otherwise repressed genes, leading to inhibition of cellular proliferation and induction of apoptosis in malignant cells. Panobinostat, analogous to other HDAC inhibitors, also induces apoptosis by directly activating cellular death receptor pathways. Preclinical data suggests that panobinostat has inhibitory activity at nanomolar concentrations and appears to be the most potent clinically available HDAC inhibitor. Here we review the current status of panobinostat and discuss its role in the treatment of solid tumors.

Keywords: LBH589; histone deacetylase inhibitor; panobinostat; solid tumors.

Figure 1

Structure of panobinostat. Note: The systematic (IUPAC) name is (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide.

Figure 2

Classes, targets and cellular distribution of HDAC inhibitors. Note: Reprinted with permission from Springer, and Dickinson M, Johnstone RW, Prince HM. Histone deacetylase inhibitors: potential targets responsible for their anticancer effect. Invest New Drugs. 2010;28(Suppl 1):S3–S20. With kind permission from Springer Science and Business Media. Abbreviation: HDAC, histone deacetylase; HDACi, histone deacetylase inhibitor.

Figure 3

Targets and downstream effects of HDAC inhibitors. Note: Reprinted with permission from Springer, and Dickinson M, Johnstone RW, Prince HM. Histone deacetylase inhibitors: potential targets responsible for their anticancer effect. Invest New Drugs. 2010;28(Suppl 1):S3–S20.11 With kind permission from Springer Science and Business Media. Abbreviations: HDACi, histone deacetylase inhibitor; HDAC, histone deacetylase; Hsp90, heat shock protein 90; STAT5, signal transducer and activator of transcription 5; p53, tumor suppressor protein 53; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells.