Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Abstract

Histone deacetylase (HDAC) inhibitors constitute a novel and growing class of anticancer agents that function by altering intracellular patterns of histone acetylation, the so-called epigenetic "histone code," thereby producing changes in cell cycle arrest, differentiation, and/or apoptosis in tumor cells. This overview describes the chemistry and preliminary characterization of recently disclosed molecules in three major classes of HDAC inhibitors: hydroxamic acids, 2-amino- benzanilides, and cyclic peptides. In addition, results from recent clinical trials on isotype-selective HDAC inhibitors are reviewed. It is clear from the plethora of new molecules and the encouraging results from clinical trials that HDAC inhibitors hold a great deal of promise, particularly as add-on therapy, for the treatment of a variety of solid and hematologic cancers.

EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor

“…Recently, we reported that the synovial sarcoma-associated SS18-SSX fusion oncoprotein dominantly inhibits EGR1 transcription through polycombmediated chromatin remodeling (Lubieniecka et al, 2008). It is noteworthy that HDAC inhibitors, a new class of anticancer drugs (Moradei et al, 2008;Stimson et al, 2009), can reverse this process. In this study, we show that EGR1 reactivation by HDAC inhibitors has a causal function in the induction of synovial sarcoma cell death by these compounds.…”

“…In fact, several HDAC inhibitors, such as FK228 (also known as romidepsin and depsipeptide), MS-275, SAHA and PXD101, are being tested in clinical trials (Moradei et al, 2008;Stimson et al, 2009), and SAHA has recently been approved for use in T-cell lymphomas (Khan and La Thangue, 2008). At the molecular and cellular levels, it is widely accepted that HDAC inhibitors suppress tumor growth by inducing cyclindependent kinase inhibitor p21/WAF1/CIP1-mediated cell cycle arrest, as well as mitochondrial/cytochrome C-dependent apoptotic cell death (Medina et al, 1997;Archer et al, 1998).…”

Epigenetic patterns of embryonic and adult stem cells

“…2,13 These findings led to the development of novel chemotherapeutic drugs including DNTM and HDAC inhibitors that are currently in clinical trials for the treatment of various cancer types. 77,78 Further analyses of normal epigenetic regulatory mechanisms and their aberrancies in cancer may lead to the discovery of new strategies for cancer diagnosis and treatment. differentiation states (e.g., comparing undifferentiated ESCs to cancer cells with a more differentiated phenotype) and not directly linked to malignancy, we analyzed if cell type-specific methylated or expressed genes are enriched for PRC targets.…”

Synthesis and Biological Evaluation of N-(Aminopyridine) Benzamide Analogues as Histone Deacetylase Inhibitors

“…25,26 To better understand the structureactivity relationship (SAR) and discover novel HDACs inhibitors with high potency and good safety profiles, we embarked on exploration of both the surface-recognition domain and the zinc binding group and on design and synthesis of N-(aminopyridine) benzamide analogues. We report here the SARs, the anti-proliferative activity and the in vivo efficacy of newly synthesized HDAC inhibitors.…”