Synthesis of a gefitinib-based chemical probe for mechanism-of-action studies

Protein kinases catalyse the phosphorylation of proteins and are key regulators of cell signalling. Aberrant kinase activity results in malignant disease, and protein kinases are major drug targets as a result. The epidermal growth factor receptor (EGFR) protein kinase is a particularly significant driver of tumorigenesis and a validated drug target for breast and lung cancers. However, EGFR drugs produce deleterious side effects in patients and encounter significant cancer resistance over 18 months. Chemical proteomics converts a drug of interest into a “chemical probe” which is used in tandem with a proteomics workflow to purify and identify protein drug targets from an endogenous context. This project successfully synthesised a light-switchable chemical probe from the drug gefitinib (EGFR inhibitor). This probe is expected to enable future identification of the cellular targets of gefitinib with precision in order to inform the mechanisms underlying its anti-proliferative effects, side effects and resistance in cancer as well as superior design principles for next generation drugs.