Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer

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Introduction The processes of absorption (A), distribution (D), metabolism (M) and excretion (E) (collectively referred as ADME assay 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; b) development of in vitro ADME assays that are predictive of in vivo behavior (PK) of drugs; 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 (HDACi) are an emerging class of therapeutic agents that induce tumor cell cytostasis, differentiation and apoptosis in various hematologic and solid malignancies. They are known to exert their anti-tumor activity by inhibiting the HDACs, which play an important role in controlling gene expression by chromatin remodeling, that affect cell cycle and survival pathways (Stimson et al., 2009). Inhibitors of histone deacetylases (HDACi) also show promising anti-inflammatory properties as demonstrated in a number of animal and cellular models of inflammatory diseases and for diabetes. The HDACi Zolinza and Romidepsin (FK228) have been approved by the FDA (United States Food and Drug Administration) for the treatment of cutaneous T cell Lymphoma (CTCL) and for peripheral T cell lymphoma as such demonstrating clinical “proof-of-principle” for this class of compounds. Four groups of HDAC inhibitors have been characterized: (i) short chain fatty acids (e.g., Sodium butyrate and phenylbutyrate), (ii) cyclic tetrapeptides , (iii) benzamides (e.g. MGCD0103 (Mocetinostat), Cl-994 and MS-275 (Entinostat)), and (iv) hydroxamic acids , LBH589 (Panabinostat), SB939 (Pracinostat), ITF2357 (Givinostat), PXD101 etc). Table 1 shows compounds that are currently in different stages of clinical development. The clinical progress that has been made by hydroxamic acid derivatives as HDAC inhibitors is of particular interest because they are usually considered as non-druggable and are down-prioritized in lead identification campaigns attributing to their poor physicochemical and ADME properties. SB939 (Pracinostat) is a potent HDACi that was discovered and developed at S*BIO (Wang et al., 2011; Novotny-Diermayr et al, 2011) to overcome some of the ADME and PK/PD (Pharmacokinetic/Pharmacodynamic) limitations of the current HDACi. The pharmacokinetics and drug metabolism aspects of the four classes of HDACi have not been reviewed extensively. In this article, we review the pharmacokinetic and drug metabolism properties of SB939 and the preclinical and clinical ADME aspects of other HDAC inhibitors in the clinic. 4.2 CI994 (N-acetyldinaline) CI994 (N-acetlydinaline), belonging to the benzamide class, is a HDACi with promising antitumor activities in preclinical xenograft models, and subsequently progressed to phase 1 2 clinical trials. CI994, a small molecule (MW=269.3) and with poor aqueous solubility, was developed as an acetylated analogue of Dinaline (GOE-1734), which, also showed equivalent antitumor activity (LoRusso et al., 1996). CI994 was eventually identified as an active metabolite of Dinaline (LoRusso et al., 1996). Limited data is available on its in vitro ADME. It showed low PPB in mice (20%) (Foster et al., 1997). In an oral PK and metabolism study in mice, where CI-994 was dosed once daily at 50 mg/kg for 14 days, it showed moderately rapid absorption (tmax= 30-45 min), 2 compartment disposition with a terminal t1/2 on day 1 (9.4 h) being longer than on day 14 (3.4 h), and oral CL ranging between 0.42 (Day 1) -0.52 (day 14) ml/min (Foster et al., 1997). High amounts of unchanged drug (42-58% of dose) were found in the urine with minimal amounts in fecal samples, suggesting that renal clearance was a major clearance pathway for CI-994. Low amounts of Dinaline were found in urine and feces indicating that in vivo conversion of CI-994 to Dinaline were not significant. In rhesus monkeys, the PK of CI-994 was characterized by low volume of distribution (Vd) (0.3 L/kg) and CL (0.05 L/h/kg), a moderate t1/2 (7.4 h), and high brain penetration (Riva et al., 2000). The oral bioavailability of CI-994 in preclinical species was 100%. In a phase 1 study in cancer patients following oral dosing (5-15 mg/m2), CI-994 showed rapid absorption, oral CL ranging between ~30-48 ml/min/m2), dose proportional increases in Cmax and AUC, and moderately long t1/2 (7.4-14 h). In the same study, no food effects were observed on the oral PK of CI-994.