Safety assessment considerations and strategies for targeted small molecule cancer therapeutics in drug discovery.

Less than 10% of all experimental drugs introduced into clinical trials ever achieve the approval of regulatory agencies for marketing. For experimental small molecule oncology therapeutics, the approval rate is even less (5%). Clinical safety and efficacy are the two main causes of failure for oncologic drugs in development. Because these failures of experimental drugs are tremendously expensive for pharmaceutical companies, strategies have been developed and refined for reducing this attrition. While these strategic activities can take place in drug development, more benefit may be gained by increasing efforts in drug discovery in the form of (1) target validation; (2) compound selectivity analysis from the perspective of balancing efficacy and toxicity; and (3) investigation of ancillary means to abrogate toxicity, especially with respect to undesirable target-related effects. Most pharmaceutical companies recognize the benefit of lead compound optimization, but the degree to which it is applied seems to vary greatly. This article presents concepts and strategies to reduce the attrition of small molecule oncology therapeutic drug candidates due to toxicity.