Small-molecule drug discovery was originally a ‘compound-based activity’. The process begins with the discovery of a biologically active compound, often a naturally occurring small molecule. The next step involves the identification of a disease that may benefit from treatment with the compound, followed by optimization and development of the eventual drug (or drugs via synthetic modifications). Penicillin is an original example of a drug that arose from this approach. Despite many advances in drug discovery in the intervening decades, compound-based drug discovery is still common today. Rapamycin, for instance, was discovered as a secondary metabolite of a Streptomyces strain and was explored without success as an antifungal agent, before emerging as an effective immunosuppressive agent (sirolimus), with derivatives being approved or investigated as therapeutics in cancer (torisel; afinitor; ridaforolimus) and in other diseases.
The ability of recombinant DNA to provide nearly unlimited access to human proteins resulted in a second approach that is also common today – ‘target-based drug discovery’. Here, therapeutic targets are selected using insights gained most often from biochemistry, cell biology and model organisms. Small molecules are identified that modulate the targets (often by small-molecule screening) followed by optimization and clinical testing. Although this is a robust process, the common failure of candidate drugs in late-stage clinical testing, due to unforeseen toxicity or lack of efficacy, reveals limits in our ability to select targets using these surrogates of human physiology.
Advances in human genetics suggest that a third approach – ‘patient-based drug discovery’ – may be most productive in the future. Molecular characterization of patient tissues is providing remarkable insights into the root cause of many disorders. As these insights often point to targets and processes that are believed to be especially challenging for small-molecule therapeutics – targets such as transcription factors, regulatory RNAs and processes such as disrupting specific protein/protein interactions – scientists have been innovating in chemistry, cell-culture science, and mechanism-of-action studies, among others. As a consequence, these ‘hard to drug’ yet key targets and processes are being pursued with new optimism.
Although heritable disorders and infectious diseases are the subject of intensive patient-based drug-discovery efforts, recent insights into the genetics and biology of human cancers have made this family of diseases a prime target for this approach. High-throughput genetic, epigenetic, and proteomic analyses of cancer tissues are providing unprecedented molecular insights into genes and pathways causally related to oncogenesis, tumor progression, and drug sensitivity and resistance. This points to a path entailing the determination of genomic features of patients’ tumors and the discovery and development of new types of therapeutics that target the dependencies (i.e., addictions) arising from the specific patterns of (epi)genetic alterations within them1
. This path has been validated in a growing number of extraordinary cases2,3
. But its generalization is a tall order, one far from the reality of current routine clinical medicine and not without additional challenges for payers, patients and healthcare providers2,4