Target identification has been considered as a chief parameter in drug discovery as it fully characterizes on-target and off-target effects of drug binding. Cell signaling receptors, structural proteins, and post-translational modifications of histones by histone deacetylases are the most widespread targets that are progressively being explored. The FDA approved histone deacetylases inhibitors and the majority of HDACi in and out of clinical trials based on the activities of 11 isoforms of the enzyme in non-selective influence approach. Unfortunately, reported HDACi does not possess a high degree of structural specificity and ultimately lessens the therapeutic index with many dose limiting toxicities. This chapter illustrates how different approaches are incorporated into the novel inhibitors discovery that are truly isoform-selective and which are specifically involved in targeting only a particular isozyme. Further, it highlights the aspects relating to provide a wider therapeutic index with an improved toxicity profile of lead like epigenetic modulators.
TopIntroduction To Cancer
Cancer is a heterogeneous disease with a wide range of clinical profile and diverse underlying mechanism. Cancer with ~14 million new cases and 8.2 million cancer-related deaths in 2012 is considered as the leading cause of morbidity and mortality worldwide. In the next two decades, the expected number of new cases of cancer is ~ 70% (Stewart & Wild, 2014).
There has been a prolonged targeting approach for the development of new cancer therapies, distinctive and appropriate for each individual. Surgery, intravenous cytotoxic chemotherapy and radiation are the major hallmark of treatment for cancer (David, 2008). These drugs target rapidly dividing cells in addition to certain normal tissues. Consequently, many patients get susceptible to therapy-related immediate and long-term toxicities like gastrointestinal symptoms, alopecia and myelosuppression that are often dose limiting.
Anti cancer drugs fail in the clinic for two main reasons; the first is that they do not act and the second is that they are not safe. Hence, innovative medications are in demand for the management of severe therapeutic conditions including cancer, autoimmune, infectious and metabolic diseases. Now, patients diagnosed with cancer very frequently shift to newer and more personalized treatment strategies. A noteworthy progress in the treatment of cancer in the past decades is the recent concept of targeted therapies which have been very much supportive in channelizing the path “from the bench to the bed” (Yoh et al., 2012).
A drug candidate is not a one size-fits-all-diseases stratagem instead its pathway has to be identified and validated appropriately. Hence, a target-based strategy for the development of new drug through drug discovery is essential. For the last two decades, researchers of biotech and pharmaceutical organisations and universities work in the area of target-based drug discovery (Terstappen et al., 2007).
There is a need for drug discovery to move from the slow and too expensive trial and error approach. Over the last two to three decades, the shift in focusing towards target based discovery has been a foremost landmark in drug discovery research. Computational modelling and drug design forms significant constituents of new-age biology for the reason that they are crucial to understand the large-scale data produced by high-throughput screening experiments and to create hypotheses, which are in general recapitulated with experimental validation.