Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

Abstract

The processes of absorption (A), distribution (D), metabolism (M) and excretion (E) (collectively referred as ADME) determine the pharmacokinetics (PK) of a compound. Lack of optimum PK is one of the major reasons for compounds to fail in the clinic resulting in high attrition rates. In the beginning of 1990, 39% of the drugs failed in the clinic due to poor PK emphasizing its importance in drug development (Waterbeemd and Gifford, 2003). In 1988, a study of the pharmaceutical companies in UK showed that non-optimal PK was one of the major reasons (~40%) for termination of drugs in development (Prentis et al., 1988). In the last two decades this number dropped to ~ 10% (Yengi et al., 2007). The main reasons for this significant drop in the number of compounds failing for PK reasons can be attributed to the following: a) application of concepts of drug metabolism and PK to design compounds in medicinal chemistry programs (Smith et al., 1996); b) development of in vitro ADME assays that are predictive of in vivo behavior (PK) of drugs (Obach et al., 1997; Venkatakrishnan et al.,2003; Pelkonen and Raunio, 2005; Thompson,2000; Fagerholm, 2007); c) use of the Lipinski rule of 5 to design oral drugs (Lipinski, 2000); d) development of computer programs to predict the human PK parameters and profiles based on in vitro ADME properties of drugs (Jamei et al., 2009); e) PK/PD correlation studies in preclinical setting and f) high throughput screening of ADME properties in in vitro and in vivo assays for hundreds of compounds in the lead identification to lead optimization stages of drug discovery. The consequence of all the above mentioned developments in ADME have resulted in the frontloading of non-drug like compounds early in drug discovery and ultimately reducing the attrition rates of compounds in the clinic. Histone acetylases (HATs) and Histone deacetylases (HDACs) are enzymes that carry out acetylation and deacetylation, respectively, of histone proteins (Minucci and Pelicci, 2006). Histone proteins form a complex with DNA called as nucleosomes, which are the structural units of chromatin. The interplay of HATs and HDACs activities regulate the structure of chromatin and control gene expression. The aberrant expression of HDACs has been linked to the pathogenesis of cancer (Minucci and Pelicci, 2006). Histone deacetylase inhibitors