Selective histone deacetylase small molecule inhibitors: recent progress and perspectives

Abstract

Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena. Areas covered: This review covers new patents and articles about isoform- or class-selective HDAC inhibitors during the last four years, as well as the therapeutic potential of these compounds. Expert opinion: HDACs represent one of the most promising therapeutic targets, particularly for tumor therapy though their roles in cancer are still blurry. From 2012 to present, along with the advances of structural biology and homology models, lots of isoform- or class-selective HDAC inhibitors, such as hydroxamic acids and benzamides with various capping groups were found, providing a promising way to circumvent drug toxicity and side-effect issues, as well as providing chemical probes for further better understanding of the biological process related to specific isoform.

Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer

“…HDAC1 has been served as a target for cancer therapy, and some small molecule HDAC inhibitors have been used in clinical treatment of patients with several types of cancer, such as T-cell lymphoma and multiple myeloma. [ 27 ] Consistent with this, the present analysis revealed the important clinical value of HDAC1 expression in lung cancer. In conclusion, HDAC1 expression might be a good biomarker for the diagnosis and prognosis of patients with lung cancer.…”

SARC018_SPORE02: Phase II Study of Mocetinostat Administered with Gemcitabine for Patients with Metastatic Leiomyosarcoma with Progression or Relapse following Prior Treatment with Gemcitabine-Containing Therapy

“…Numerous clinical trials have been performed to identify clinical activity of HDAC inhibitors in patients with solid tumors. Although HDAC inhibitors have shown success in preventing graft versus host disease (GVHD) [ 61 ] and treating patients with T-cell lymphoma [ 62 ] and multiple myeloma [ 63 , 64 ]; to date, no study has shown significant benefit in patients with solid tumors [ 65 , 66 ]. We sought to explore the potential for HDAC inhibition to reverse chemoresistance based on promising results seen in animal models of leiomyosarcoma.…”

Epigenetics and Bone Remodeling

“…The best studied epigenetic histone mark is acetylation; the addition and removal of acetyl groups occurs via the action of histone acetyltransferases and histone deacetylases. This is of particular clinical relevance, as histone deacetylases are the target of a number of drugs, mostly used as cancer therapy [66]. There are 18 human histone deacetylases (HDACs), falling into four broad classes, and several studies have examined the impacts of HDAC inhibitors on bone formation and maturation.…”