Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.
Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. mmottama@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. mmottama@xula.edu.
Madhusoodanan
M
Mottamal
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. szheng@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. szheng@xula.edu.
Shilong
S
Zheng
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. thuang@xula.edu.|College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA. thuang@xula.edu.
Tien L
TL
Huang
RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA. gwang@xula.edu.|Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. gwang@xula.edu.
Guangdi
G
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000068456:Clinical Studies as Topic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases