Abstract

The discovery of small molecule anticancer drugs greatly benefits from the parallel development of chemical tools to investigate target biology and define the path to the clinic. The integration of largescale chemical, genomic and structural information enhances target selection and prioritisation, while the early identification of chemical tools validates pharmacological modulation as a therapeutic strategy. Chemical feasibility or 'druggability' is critical in prioritising targets for drug discovery, especially those from less established therapeutic classes, and influences the choice of strategy to find chemical starting points. Not all chemical tools are suitable for target validation studies or as starting points for drug discovery, and a compound's physicochemical properties and selectivity are necessary factors to be considered. Using small molecule tools to identify pharmacodynamic biomarkers is essential to support optimisation of drug candidates and to translate preclinical findings into patients. Importantly, new chemical tools often lead to new biological findings and can change the proposed path to the clinic for modulators of a given cancer target. Examples from our research on oncogenic signal transduction and DNA damage response pathways show how targets are selected and prioritised for research, and how fit-for-purpose chemical tools have been used to validate targets for study, to identify potential clinical contexts and patient stratification, to define pharmacodynamic biomarkers predictive of target engagement and efficacy, and to establish combination scheduling strategies to inform the clinical development of candidate inhibitors.