Targeted Small Molecule Drug Discovery

Abstract

Cancer drug discovery starts with selection of target or phenotype to screen against and culminates in the nomination of a molecule that is ready for human testing. Target validation comprises a package of data from human genetics and preclinical models implicating the target as a driver of cancer. Ideally, dependency on the target is linked to a biomarker-defined patient population that is expected to respond to the targeted agent. Even for target agnostic phenotypic screening, deconvolution of the molecular target is still critical for advancing screening hits toward compounds with drug-like properties and for the planning of early clinical trials. The identification of small molecule modulators against a target begins with screening to generate chemical starting points. Medicinal chemists, working with discovery biologists, advance these chemicals through repeated cycles of synthetic modification and functional assays to arrive at molecules with the desired behavior. Despite growing knowledge of the rules governing chemical structure and biologic function, this process is fraught with false starts and blind alleys. A system of stage gates with specific requirements for advancing from one stage to the next can help to manage resources appropriately during discovery.