challenge of selectivity within a target family

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Targets selected for a drug discovery program are rarely isolated, unique targets. They very often are members of families of enzymes or receptors that share related functions. Sometimes these families are small, with just a very few members, but other families are massive with over 100 different members. These different members all have related functionality, and that similar functionality often arises from related protein structure. So, these targets often have similar sequence homology, especially around the binding pocket and in the active site. Therefore, it may not be surprising that achieving a high level of selectivity for a specific member within a family can be difficult. Of course, poor selectivity is a potential source of safety risks and adverse drug reactions. This entire idea of selectivity within a family of targets is properly an example of off-target selectivity.
How can a drug team discover compounds that demonstrate selectivity within a pool of such similar targets? First, the family members may be similar in structure, but they are not identical. Structural differences in the target can often be exploited to boost selectivity. Different family members may have different expression levels in different tissues. So, although you may administer a compound systemically, if compound distribution can be managed, such as primarily to the liver or central nervous system, it may be possible to hit one target family member over another. Clearly, all these approaches require considerable knowledge of the target and the target family through molecular biology and structural biology research.
Protein kinases are a massive family – arguably a superfamily – of targets. Protein kinases are enzymes or receptors with enzymatic activity that phosphorylate proteins in cell signaling cascades, especially associated with cell growth and cancer. There are nearly 600 protein kinases – often collectively called the kinome. An important subfamily in the kinome includes the tyrosine kinases with nearly 100 members. These are very common targets for oncology programs. To the right are some examples of specific tyrosine kinases – the epidermal growth factor receptor. VEGFR – vascular epidermal growth factor receptor. There are, of course, many others. Assay panels for various protein kinases are used to monitor the selectivity of new compounds to predict possible safety risks.
Phosphodiesterases or PDEs are another family – again arguably a superfamily. PDEs catalyze the hydrolysis of cyclic AMP or cyclic GMP to shut down signal cascades. The families run from PDE1 through PDE11 with many additional subdivisions, like PDE4C1, etc. All the PDEs are intracellular enzymes. The therapeutic indications for PDEs can vary. PDE5 is the target for sildenafil. That is Viagra, which treats erectile dysfunction. PDE3 has been targeted as a vasodilator for heart failure. PD4, excuse me… PDE4 has been used to treat chronic obstructive pulmonary disease. So, with potential use in various indications, designing compounds with selectivity across the various PDEs or within a family is vital for safety. Assays, in vitro assays, are available for determining selectivity of new compounds.