Rare haplotypes, which per se apparently do not represent particularly favorable drug targets, may nevertheless require particular attention
as potential mediators of severe side effects and may constitute significant, fractions of individual gene sequences resulting in the same protein isoform25 or share a common pattern conferring risk.29 Finally, as outlined earlier, any extreme may be possible: this may include, at the one end of the spectrum, completely invariable genes that may amount to about, 20% of all genes and, at the other end, highly decomposed genes with frequencies of numerous sequence haplotypes not exceeding 4%, for instance. Obviously, a drug target is the more attractive if it has a low variability Inhibitors,research,lifescience,medical and decomposition into different haplotype(s) (classes) and protein
isoforms. In this context, the modern version of a blockbuster drug target in the postgenome Inhibitors,research,lifescience,medical age of genetic variation would be an invariable gene. The pharmaccutically most attractive component of a proposed catalogue of all haplotypes of all genes as the ultimate biomedical resource would probably be the specific fraction containing the most, invariable genes. In reality though, we may have to concentrate on manageable variability, ie, scenarios where variability is limited or the functional implications Inhibitors,research,lifescience,medical are clearly definable. If a drug has not been tailored a priori to the target, in its variable, naturally occurring forms, incompatibilities, ineffectiveness, and adverse side effects will become apparent sooner or later. The molecular truth will eventually Inhibitors,research,lifescience,medical take its toll on both individuals and the pharmaceutical industry. Any developments that are driven by the vision of a personalized medicine11-14 will have to be based on knowledge of the molecular diversity of potential drug targets and, generally, of any genes involved in drug action and metabolism.9,85,86 Inhibitors,research,lifescience,medical This information will be essential for decision-making processes. It will also be valuable in guiding in vitro screens and their specific experimental design. It will allow an extrapolation of drug response in population segments, as well as a correlation
of in vitro and in vivo responsiveness (in conjunction with information PD184352 (CI-1040) on the genetic makeup of drug-metabolizing enzymes and competing, homologous targets). The integration of knowledge on human genetic variation into all phases of drug development, and application will be one of the pharmaceutical BMS-907351 clinical trial industry’s major future tasks. Last but not least, what does the evidence for gene decomposition into multiple forms tell us about, the prospects for an individualized medicine?11-14,87 The fact, that individual sequence differences exist, does not, mean that tailoring drugs to each individual is possible or feasible. Given the remarkable genetic diversity and its challenges, this vision may seem somewhat too bold and unrealistic at this stage.