Before addressing this question an understanding of which criteria define a 'good' drug target and how such targets have been discovered historically is instructive. While biologics, such as peptide and antibody-based drugs, address targets as well, the scope of this chapter is confined to the discussion of drug targets addressed by small molecules. A cynic's definition of a good drug target would be a target which is already successfully addressed by a marketed small molecule such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with Lipitor,4 or BCR-abl with Gleevec.5 However apt this definition may be, it is too subjective and relies heavily on circular reasoning. Instead, a pragmatist would define a molecular target as one with a proven crucial role in causation or symptoms of a human disease, which when targeted in the clinic with a small molecule leads to reversal or diminishment of the disease and/or symptoms. Again, this definition invokes the requirement of a small molecule a priori to define what makes a good drug target, and with good reason. Many of the first and best drug targets were discovered with a proven small molecule in hand. For instance, the well-known immunosuppressant drug cyclosporine A (CsA) was used as a probe to purify its target cyclophilin which modulates FK506 binding protein (FKBP) activity for the treatment of transplant rejection.6 Metformin (glucophage) which modulates adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase activity in the treatment of diabetes7 has led to programs targeting each with small-molecule modulators. Many successful antibiotics such as the beta-lactams and even penicillin were used to discover their targets which led to subsequent target-based lead finding programs.8 So, while it is often the case that drugs themselves provide direct rationale for their targeted gene products as drug targets, these define a limited set of validated targets, totaling approximately 120 based on all marketed drugs.2 In these instances, the question of druggability and target validity are answered simultaneously, but in order to evaluate novel putative targets, one needs to separate out these two requirements of a 'good' drug target and systematically mine and analyze the genome for optimal target opportunities.
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